U.S. patent application number 15/529786 was filed with the patent office on 2018-02-01 for compounds.
The applicant listed for this patent is New Pharma Licence Holdings Limited. Invention is credited to Steven Boakes, Pamela Brown, Michael Dawson, Esther Duperchy, Stephen Frederick Moss, Mona Simonovic, Steven James Stanway, Antoinette Wilson.
Application Number | 20180030092 15/529786 |
Document ID | / |
Family ID | 54705181 |
Filed Date | 2018-02-01 |
United States Patent
Application |
20180030092 |
Kind Code |
A1 |
Brown; Pamela ; et
al. |
February 1, 2018 |
COMPOUNDS
Abstract
The present invention provides a compound of formula (I), and
its use in methods of treatment, including the treatment of
bacterial infections. Methods for the preparation of the compound
of formula (I) are also provided. The compound of formula (I) has
the structure shown below, where --R.sup.6 and --R.sup.7 are each
together with the carbonyl group and nitrogen alpha to the carbon
to which it is attached an amino acid residue, except that R6
together with the carbonyl group and nitrogen alpha to the carbon
to which it is attached is not a phenylalanine, leucine or valine
residue and/or --R.sup.7 together with the carbonyl group and
nitrogen alpha to the carbon to which it is attached is not a
leucine, iso-leucine, phenylalanine, threonine, valine or
nor-valine residue, and --T, A.sup.1, A.sup.2, A.sup.3 and
--R.sup.10 are as discussed in the application: ##STR00001##
Inventors: |
Brown; Pamela; (Reading,
GB) ; Dawson; Michael; (Reading, GB) ;
Simonovic; Mona; (Reading, GB) ; Boakes; Steven;
(Reading, GB) ; Duperchy; Esther; (Reading,
GB) ; Stanway; Steven James; (Ongar, GB) ;
Wilson; Antoinette; (Ongar, GB) ; Moss; Stephen
Frederick; (Ongar, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
New Pharma Licence Holdings Limited |
Valletta |
|
MT |
|
|
Family ID: |
54705181 |
Appl. No.: |
15/529786 |
Filed: |
November 26, 2015 |
PCT Filed: |
November 26, 2015 |
PCT NO: |
PCT/EP2015/077821 |
371 Date: |
May 25, 2017 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
Y02A 50/475 20180101;
Y02A 50/481 20180101; Y02A 50/30 20180101; Y02A 50/478 20180101;
A61P 31/04 20180101; C07K 7/62 20130101; A61K 38/00 20130101 |
International
Class: |
C07K 7/62 20060101
C07K007/62 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 26, 2014 |
GB |
1421020.7 |
Sep 10, 2015 |
GB |
1516059.1 |
Claims
1. A compound of formula (I): ##STR00283## wherein: -T is
R.sup.T-X--; -A.sup.1- is absent or is an amino acid residue;
-A.sup.2- is an amino acid residue selected from threonine and
serine, such as L-threonine and L-serine; -A.sup.3- is an amino
acid residue represented by: ##STR00284## where the asterisk is the
point of attachment to -A.sup.2-, and --R.sup.3 is C.sub.1-6 alkyl,
such as C.sub.1-4, having one amino or one hydroxyl substituent;
--X-- is --C(O)--, --NHC(O)--, --OC(O)--, --CH.sub.2-- or
--SO.sub.2--; --R.sup.T is a terminal group containing hydroxyl
and/or amino functionality, and where -A.sup.1- is absent,
R.sup.T-X-- is not an .alpha.-amino acid residue having a free
.alpha.-amino group (--NH.sub.2), where the .alpha.-amino acid
residue is selected from the group consisting of Ala, Ser, Thr,
Val, Leu, Ile, Pro, Phe, Tyr, Trp, His, Lys, Arg,
.alpha.,.gamma.-diaminobutyric acid (Dab) and
.alpha.,.beta.-diaminopropionic acid (Dap); --R.sup.6 together with
the carbonyl group and nitrogen alpha to the carbon to which it is
attached is an amino acid residue; --R.sup.7 together with the
carbonyl group and nitrogen alpha to the carbon to which it is
attached is an amino acid residue; and --R.sup.6 together with the
carbonyl group and nitrogen alpha to the carbon to which it is
attached is not a phenylalanine, leucine or valine residue and/or
--R.sup.7 together with the carbonyl group and nitrogen alpha to
the carbon to which it is attached is not a leucine, iso-leucine,
phenylalanine, threonine, valine or nor-valine residue; R.sup.10
together with the carbonyl group and nitrogen alpha to the carbon
to which it is attached, is a threonine or leucine residue; and
salts, solvates, protected forms and/or prodrug forms thereof.
2. The compound of claim 1, wherein --R.sup.6 together with the
carbonyl group and nitrogen alpha to the carbon to which it is
attached is not a phenylalanine, leucine or valine residue.
3. The compound of claim 2, wherein --R.sup.7 together with the
carbonyl group and nitrogen alpha to the carbon to which it is
attached is a leucine, iso-leucine, phenylalanine, threonine,
valine or nor-valine residue.
4. The compound of claim 1, wherein --R.sup.6 is C.sub.1-12 alkyl,
C.sub.0-12 alkyl(C.sub.3-10 cycloalkyl), C.sub.0-12
alkyl(C.sub.3-10 heterocyclyl) or C.sub.0-12 alkyl(C.sub.5-10
aryl), where the C.sub.1-12 alkyl, C.sub.3-10 cycloalkyl group
C.sub.3-10 heterocyclyl group, and the C.sub.5-10 carboaryl group
are optionally substituted.
5. The compound of claim 4, wherein --R.sup.6 is C.sub.0-12
alkyl(C.sub.5-10 aryl), where the C.sub.5-10 carboaryl group is
optionally substituted.
6-7. canceled
8. The compound of claim 5, wherein the C.sub.5-10 aryl group is
substituted with one or more groups --R.sup.Z, where each group
--R.sup.Z is selected from halo, optionally substituted C.sub.1-12
alkyl, optionally substituted C.sub.2-12 alkenyl, optionally
substituted C.sub.2-12 alkynyl, optionally substituted C.sub.3-10
cycloalkyl, optionally substituted C.sub.3-10 heterocyclyl,
optionally substituted C.sub.5-12 aryl, --CN, --NO.sub.2,
--OR.sup.Q, --N(R.sup.W)C(O)R.sup.Q, --N(R.sup.Q).sub.2, and
--C(O)N(R.sup.Q).sub.2, where --R.sup.W is H or C.sub.1-4 alkyl;
and --R.sup.Q is H or --R.sup.Q1, and --R.sup.Q1 is selected from
optionally substituted C.sub.1-12 alkyl, C.sub.2-12 alkenyl,
C.sub.2-12 alkynyl, and C.sub.5-12 aryl, and in a group
--N(R.sup.Q).sub.2 the groups --R.sup.Q may together with the
nitrogen atom to which they are attached form a C.sub.5-6
heterocycle, where the heterocycle is optionally substituted.
9-15. canceled
16. The compound of claim 5, wherein C.sub.0-12 alkyl(C.sub.5-10
aryl) is C.sub.1 alkyl(C.sub.5-10 aryl).
17. The compound of claim 4, wherein --R.sup.6 is C.sub.0-12
alkyl(C.sub.3-10 cycloalkyl), where the C.sub.3-10 cycloalkyl group
is optionally substituted.
18. canceled
19. The compound of claim 17, wherein the C.sub.3-10 cycloalkyl
group is unsubstituted.
20. The compound of claim 17, wherein the C.sub.3-10 cycloalkyl
group is substituted with one or more groups --R.sup.Z, where each
group --R.sup.Z is selected from halo, optionally substituted
C.sub.1-12 alkyl, optionally substituted C.sub.2-12 alkenyl,
optionally substituted C.sub.2-12 alkynyl, optionally substituted
C.sub.3-10 cycloalkyl, optionally substituted C.sub.3-10
heterocyclyl, optionally substituted C.sub.5-12 aryl, --CN,
--NO.sub.2, --OR.sup.Q, --SR.sup.Q, --N(R.sup.W)C(O)R.sup.Q,
--N(R.sup.Q).sub.2, and --C(O)N(R.sup.Q).sub.2, where --R.sup.W is
H or C.sub.1-4 alkyl; and --R.sup.Q is H or --R.sup.Q1, and
--R.sup.Q1 is selected from optionally substituted C.sub.1-12
alkyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, and C.sub.5-12 aryl,
and in a group --N(R.sup.Q).sub.2 the groups --R.sup.Q may together
with the nitrogen atom to which they are attached form a C.sub.5-6
heterocycle, where the heterocycle is optionally substituted.
21. The compound of claim 17, wherein C.sub.0-12 alkyl(C.sub.3-10
cycloalkyl) is C.sub.1 alkyl(C.sub.3-10 cycloalkyl).
22. The compound according to claim 4, wherein --R.sup.6 is
optionally substituted C.sub.1-12 alkyl.
23-24. canceled
25. The compound according to claim 1, wherein: (i) -A.sup.1- is
absent; and/or (ii) A.sup.2- is L-threonine or L-serine; and/or
(iii) R.sup.3 together with the carbonyl group and nitrogen alpha
to the carbon to which it is attached, is
.alpha.,.gamma.-diaminobutyric acid (Dab) or .alpha.,62
-diaminopropionic acid (Dap); and/or (iv) R.sup.10 together with
the carbonyl group and nitrogen alpha to the carbon to which it is
attached is a threonine residue, such as L-threonine; and/or (v)
X-- is --C(O)--.
26-31. canceled
32. The compound according to claim 1, wherein --R.sup.T is an
amino-containing group: ##STR00285## where: --R.sup.A is hydrogen
or -L.sup.A-R.sup.AA; -Q- is a covalent bond or --CH(R.sup.B)--;
--R.sup.B is hydrogen or -L.sup.B-R.sup.BB; or, where -Q- is
--CH(R.sup.B)--, --R.sup.A and --R.sup.B together form a 5- to
10-membered monocyclic or bicyclic carbocycle, or --R.sup.A and
--R.sup.B together form a 5- to 10-monocyclic or bicyclic
heterocycle; and, where -Q- is a covalent bond --R.sup.A is
-L.sup.A-R.sup.AA, and where -Q- is --CH(R.sup.B)-- one or both of
--R.sup.A and --R.sup.B is not hydrogen; --R.sup.16 is
independently hydrogen or C.sub.1-4 alkyl; --R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl; or --NR.sup.16R.sup.17
is a guanidine group; or --R.sup.17 and --R.sup.A together form a
5- to 10-membered nitrogen-containing monocyclic or bicyclic
heterocycle; or, where -Q- is --CH(R.sup.B)--, --R.sup.17 and
--R.sup.B together form a 5- to 10-membered nitrogen-containing
monocyclic or bicyclic heterocycle; and where --R.sup.17 and
--R.sup.A together form a monocyclic nitrogen-containing
heterocycle, each ring carbon atom in --R.sup.17 and --R.sup.A is
optionally mono- or di-substituted with --R.sup.C, and the
monocyclic heterocycle is substituted with at least one group
selected from --R.sup.C, --R.sup.N, --R.sup.NA and
-L.sup.B-R.sup.BB, where present, and where --R.sup.17 and
--R.sup.B together form a monocyclic nitrogen-containing
heterocycle, each ring carbon atom in --R.sup.17 and --R.sup.B is
optionally mono- or di-substituted with --R.sup.C, and the
monocyclic heterocycle is substituted with at least one group
selected from --R.sup.C, and --R.sup.N, where present, or the
monocyclic heterocycle is optionally substituted when --R.sup.A is
-L.sup.A-R.sup.AA, and a monocyclic nitrogen-containing heterocycle
optionally contains one further nitrogen, oxygen or sulfur ring
atom, and where a further nitrogen ring atom is present it is
optionally substituted with --R.sup.N, with the exception of a
further nitrogen ring atom that is connected to the carbon that is
a to the group --X--, which nitrogen ring atom is optionally
substituted with --R.sup.NA; where --R.sup.17 and --R.sup.A or
--R.sup.17 and --R.sup.B together form a bicyclic
nitrogen-containing heterocycle, each ring carbon atom in
--R.sup.17 and --R.sup.A or --R.sup.17 and --R.sup.B is optionally
mono- or di-substituted with --R.sup.D; and the bicyclic
nitrogen-containing ring atom heterocycle optionally contains one,
two or three further heteroatoms, where each heteroatom is
independently selected from the group consisting of nitrogen,
oxygen and sulfur, and where further nitrogen ring atoms are
present, each further nitrogen ring atom is optionally substituted
with --R.sup.N, with the exception of a nitrogen ring atom that is
connected to the carbon that is a to the group --X--, which
nitrogen ring atom is optionally substituted with --R.sup.NA; where
--R.sup.A and --R.sup.B together form a 5- to 10-membered
monocyclic carbocycle or heterocycle, each ring carbon atom in
--R.sup.A and --R.sup.B is optionally mono- or di-substituted with
--R.sup.C, and a nitrogen ring atom, where present in the
monocyclic heterocycle, is optionally substituted with --R.sup.N,
with the exception of a nitrogen ring atom that is connected to the
carbon that is a to the group --X--, which nitrogen ring atom is
optionally substituted with --R.sup.NA; where --R.sup.A and
--R.sup.B together form a 5- to 10-membered bicyclic carbocycle or
heterocycle, each ring carbon atom in --R.sup.A and --R.sup.B is
optionally mono- or di-substituted with --R.sup.D, and a nitrogen
ring atom, where present in the bicyclic heterocycle, is optionally
substituted with --R.sup.N, with the exception of a nitrogen ring
atom that is connected to the carbon that is a to the group --X--,
which nitrogen ring atom is optionally substituted with --R.sup.NA;
and where R.sup.17 and --R.sup.A or --R.sup.17 and --R.sup.B
together form a 5- to 10-membered nitrogen-containing monocyclic or
bicyclic heterocycle, or where --R.sup.A and --R.sup.B together
form a 5- to 10-membered monocyclic or bicyclic carbocycle, or
together form a 5- to 10-membered monocyclic or bicyclic
heterocycle, a carbon ring atom in --R.sup.17 and --R.sup.A,
--R.sup.17 and --R.sup.B, or --R.sup.A and --R.sup.B is optionally
alternatively substituted with oxo (.dbd.O); each --R.sup.C is
independently -L.sup.C-R.sup.CC; each --R.sup.D is independently
selected from --R.sup.C, halo, --NO.sub.2, --OH, and --NH.sub.2;
each --R.sup.N is independently -L.sup.N-R.sup.NN; each --R.sup.NA
is independently --R.sup.L--R.sup.NN or --R.sup.NN; --R.sup.AA,
--R.sup.BB, and each --R.sup.CC and --R.sup.NN where present, is
independently selected from C.sub.1-12 alkyl, C.sub.3-10
cycloalkyl, C.sub.4-10 heterocyclyl, and C.sub.5-12 aryl; each
-L.sup.A- is independently a covalent bond or a linking group
selected from --R.sup.L--*, --O-L.sup.AA-*, --OC(O)-L.sup.AA-*,
--N(R.sup.11)-L.sup.AA-*, and --C(O)-L.sup.AA-*, where the asterisk
indicates the point of attachment of the group -L.sup.A- to
--R.sup.AA; each -L.sup.B- and -L.sup.C- is independently a
covalent bond or a linking group selected from --R.sup.L--*,
--O-L.sup.AA-*, --OC(O)-L.sup.AA-*, --N(R.sup.11)-L.sup.AA-*,
--N(R.sup.11)C(O)-L.sup.AA-*, --C(O)-L.sup.AA-*,
--C(O)O-L.sup.AA-*, and --C(O)N(R.sup.11)- L.sup.AA-* and
optionally further selected from --N(R.sup.11)S(O)-L.sup.AA-*,
--N(R.sup.11)S(O).sub.2-L.sup.AA-*, --S(O)N(R.sup.11)-L.sup.AA-*,
and --S(O).sub.2N(R.sup.11)-L.sup.AA-* where the asterisk indicates
the point of attachment of the group -L.sup.B- to --R.sup.BB or the
group -L.sup.C- to --R.sup.CC; each -L.sup.N- is independently a
covalent bond or a group selected from --S(O)-L.sup.AA-*,
--S(O).sub.2-L.sup.AA-*, --C(O)-L.sup.AA-* and
--C(O)N(R.sup.11)-L.sup.AA-*, where the asterisk indicates the
point of attachment of the group -L.sup.N- to --R.sup.NN; and each
-L.sup.AA- is independently a covalent bond or --R.sup.L--; and
each --R.sup.L- is independently selected from C.sub.1-12 alkylene,
C.sub.2-12 heteroalkylene, C.sub.3-10 cycloalkylene and C.sub.5-10
heterocyclylene, and where -L.sup.AA- is connected to a group
C.sub.1-12 alkyl, --R.sup.L- is not C.sub.1-12 alkylene; and each
C.sub.1-12 alkyl, C.sub.3-10 cycloalkyl, C.sub.4-10 heterocyclyl,
C.sub.5-12 aryl, C.sub.1-12 alkylene, C.sub.2-12 heteroalkylene,
C.sub.3-10 cycloalkylene and C.sub.5-10 heterocyclylene group is
optionally substituted, where --R.sup.S is an optional substituent
to carbon and --R.sup.12 is an optional substituent to nitrogen;
each --R.sup.S is independently selected from --OH, --OR.sup.12,
--OC(O)R.sup.12, --OC(O)R.sup.12, halo, --R.sup.12, --NHR.sup.12,
--NR.sup.12R.sup.13, --NHC(O)R.sup.12, --N(R.sup.12)C(O)R.sup.12,
--SH, --SR.sup.12, --C(O)R.sup.12, --C(O)OH, --C(O)OR.sup.12,
--C(O)NH.sub.2, --C(O)NHR.sup.12 and C(O)NR.sup.12R.sup.13, except
that --R.sup.12 is not a substituent to a C.sub.1-12 alkyl group;
or where a carbon atom is di-substituted with --R.sup.S, these
groups may together with the carbon to which they are attached form
a C.sub.3-6 carbocycle or a C.sub.5-6 heterocycle, where the
carbocycle and the heterocycle are optionally substituted with one
or more groups --R.sup.12; each --R.sup.12 is independently
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, phenyl or benzyl; each
--R.sup.13 is independently C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
phenyl or benzyl; or --R.sup.12 and --R.sup.13, where attached to
N, may together form a 5- or 6-membered heterocyclic ring, which is
optionally substituted with C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
phenyl or benzyl; each --R.sup.11 is independently hydrogen or
C.sub.1-4 alkyl.
33. A compound of formula (II): ##STR00286## wherein: -T.sup.A is
hydrogen, C.sub.1-4 alkyl or R.sup.N--X--; -A.sup.1- is absent or
is an amino acid residue; -A.sup.2- is absent or is an amino acid
residue; -A.sup.3- is absent or is an amino acid residue; --X-- is
--C(O)--, --NHC(O)--, --OC(O)--, --CH.sub.2-- or --SO.sub.2--;
--R.sup.N is a terminal group; --R.sup.6A is C.sub.1-12 alkyl,
C.sub.0-12 alkyl(C.sub.3-10 cycloalkyl), C.sub.0-12
alkyl(C.sub.3-10 heterocyclyl) or C.sub.0-12 alkyl(C.sub.5-10
aryl), where the C.sub.1-12 alkyl, C.sub.3-10 cycloalkyl group
C.sub.3-10 heterocyclyl group, and the C.sub.5-10 aryl group are
optionally substituted, with the proviso that --R.sup.6A is not
benzyl, iso-butyl, iso-propyl, 4-phenylphen-1-yl methyl,
--(CH.sub.2).sub.7CH.sub.3, 4--(OBn)-phen-1-yl methyl or
--CH.sub.2S(CH.sub.2).sub.5CH.sub.3; -R.sup.7A together with the
carbonyl group and nitrogen alpha to the carbon to which it is
attached is an amino acid residue; R.sup.10 together with the
carbonyl group and nitrogen alpha to the carbon to which it is
attached, is a threonine or leucine residue; and salts, solvates,
protected forms and/or prodrug forms thereof.
34. The compound according to claim 33, wherein --R.sup.6A is: (i)
--C.sub.0-12 alkyl(C.sub.5-10 aryl), where the C.sub.5-10 carboaryl
group is optionally substituted; or (ii) C.sub.0-12
alkyl(C.sub.3-10 cycloalkyl), where the C.sub.3-10 cycloalkyl is
optionally substituted.
35-43. canceled
44. The compound according to claim 33, wherein: (i) -A.sup.1- is
absent; and/or (ii) A.sup.2- is L-threonine or L-serine; and/or
(iii) R.sup.3 together with the carbonyl group and nitrogen alpha
to the carbon to which it is attached, is
.alpha.,.gamma.-diaminobutyric acid (Dab) or
.alpha.,.beta.-diaminopropionic acid (Dap), such as L-Dab or L-Dap;
and/or (iv) R.sup.10 together with the carbonyl group and nitrogen
alpha to the carbon to which it is attached is a threonine residue,
such as L-threonine-, and/or (v) X-- is --C(O)--.
45-49. canceled
50. The compound according to claim 33, wherein --R.sup.T contains
hydroxyl and/or amino functionality.
51. A pharmaceutical composition comprising a compound according to
claim 1 or a compound according to claim 50.
52. canceled
53. A method of treating a microbial infection in a patient,
comprising administering compound according to claim 1 or a
compound according to claim 50 the method comprising the step of
administering a compound of claim 1 or a compound of claim 15 to a
patient in need thereof.
54. canceled
55. A method according to claim 53, wherein the microbial infection
is a Gram-negative bacterial infection.
56-73. canceled
Description
RELATED APPLICATIONS
[0001] The present case is related to GB 1421020.7 filed on 26 Nov.
2014 (26.11.2014) and GB 1516059.1 filed on 10 Sep. 2015
(10.09.2015), the contents of both of which are hereby incorporated
by reference in their entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to novel polymyxin compounds,
combinations of compounds, pharmaceutical compositions comprising
the compounds and the use of the compounds, pharmaceutical
compositions and combinations for treatment, for example treatment
of microbial infections, particularly by Gram-negative
bacteria.
BACKGROUND
[0003] In susceptible individuals, certain Gram-negative bacteria
such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas
aeruginosa and Acinetobacter baumanii can cause serious infections,
such as pneumonia, urinary tract infections, skin and skin
structure infections such as wound infections, ear infections, eye
infections, intra-abdominal infections, bacterial overgrowth in the
gastrointestinal tract and bacteraemia/sepsis. The treatment of
serious bacterial infections in clinical practice can be
complicated by antibiotic resistance. Recent years have seen a rise
in infections by Gram-negative bacteria which are resistant to many
types of antimicrobials including broad spectrum antibiotics such
as aminoglycosides, cephalosporins and even carbapenems. There is
therefore a need to identify new antimicrobials that are effective
against Gram-negative bacteria, in particular against multidrug
resistant Gram-negative bacteria.
[0004] Polymyxins are a class of antibiotics produced by the
Gram-positive bacterium Bacillus polymyxa. First identified in the
late 1940s, polymyxins, particularly polymyxin B and polymyxin E
(colistin, usually as its prodrug colistin methane sulphonate) were
used in the treatment of Gram-negative infections. However, these
antibiotics exhibited side effects such as neurotoxicity and
nephrotoxicity. Nevertheless the polymyxins now play an important
role in the therapy of MDR Gram-negative infections due to the lack
of viable alternatives. However, their use in therapy is limited to
treatment of last resort.
[0005] WO 2008/017734 tries to address this toxicity problem by
providing polymyxin derivatives carrying at least two but no more
than three positive charges. These compounds are said to be
effective antibacterial agents with reduced renal toxicity. It is
hypothesised in the disclosure that the reduced number of positive
charges decreases the affinity of the compound for isolated rat
kidney tissue which in turn may lead to a reduction in
nephrotoxicity.
[0006] Certain des-fatty acyl polymyxin derivatives have also been
disclosed with reduced acute toxicity in mice whilst retaining good
activity against pseudomonads (Katsuma et al. Chem. Pharm. Bull.
2009; 57, 332-336; Sato et al. Chem. Pharm. Bull. 2011; 59,
597-602). The compounds were significantly less active than
polymyxin B against E. coli and K. pneumoniae.
[0007] WO 2010/075416 provides urea linked aryl polymyxin
decapeptides including CB182,804, which is reported to have similar
activity but reduced renal toxicity compared with polymyxin B.
Phenyl cyclopropane polymyxin derivatives are also described in
U.S. Pat. No. 8,415,307. These compounds are shown to have similar
or reduced activity compared with polymyxin B.
[0008] WO 2012/168820 provides a further series of polymyxin
derivatives reported to have reduced toxicity, and sometimes
enhanced activity compared with polymyxin B, in which the
diaminobutyrate group at position 3 in the tripeptide side chain is
replaced by a diaminopropionate moiety.
[0009] WO 2015/149131 and Velkov et al. describe modified polymyxin
compounds. Typically these compounds retain a fatty acyl group at
the N terminal of a polymyxin decapeptide, including, for example,
an octanoyl or a nonanoyl group.
[0010] There remains a need for less toxic polymyxin derivatives
which offer therapeutic preparations with consistently potent
activity across the target pathogens and acceptable toxicity.
[0011] The present inventors have previously described in WO
2013/072695, TW 101142961 and GCC 2012/22819, the contents of each
of which are hereby incorporated in their entirety, polymyxin
compounds for use in the treatment of microbial infections.
[0012] The present inventors have also described in WO 2014/188178
and WO 2015/135976, the contents of both of which are hereby
incorporated in their entirety, alternative polymyxin compounds for
use in the treatment of microbial infections. In particular, WO
2014/188178 describes modifications to the N terminal of polymyxin
decapeptides and nonapeptides. WO 2015/135976 describes
modifications to the N terminal of polymyxin nonapeptides.
[0013] Surprisingly, the present inventors have found certain
polymyxin derivatives which have reduced toxicity compared to
polymyxin or colistin and are particularly active against
[0014] Gram-negative bacteria, including bacterial strains with
decreased susceptibility to polymyxin B and/or and polymyxin E.
These agents thus offer therapeutic options of consistently potent
activity, but lower toxicity than currently available
therapies.
SUMMARY OF THE INVENTION
[0015] In a general aspect the present invention provides a
polymyxin compound of formula (I) or formula (II), as described
herein, and its use in a method of treatment or prophylaxis, and
optionally in combination with a second agent (which may be
referred to as an active agent). The compounds of formula (I) of
formula (II) may be used to treat a microbial infection, such as a
Gram-negative bacterial infection.
[0016] In a first aspect of the invention, there is provided a
compound of formula (I), and pharmaceutically acceptable salts and
solvates thereof. The compound of formula (I) is represented
thus:
##STR00002##
[0017] wherein:
[0018] -T is R.sup.T-X--;
[0019] -A.sup.1- is absent or is an amino acid residue;
[0020] -A.sup.2- is an amino acid residue selected from threonine
and serine, such as L-threonine and L-serine;
[0021] -A.sup.3- is an amino acid residue represented by:
##STR00003##
[0022] where the asterisk is the point of attachment to -A.sup.2-,
and --R.sup.3 is C.sub.1-6 alkyl, such as C.sub.1-4, having one
amino or one hydroxyl substituent;
[0023] --X-- is --C(O)--, --NHC(O)--, --OC(O)--, --CH2-- or
--SO.sub.2--;
[0024] --RT is a terminal group containing hydroxyl and/or amino
functionality, and where -A.sup.1- is absent, R.sub.T-X-- is not an
.alpha.-amino acid residue having a free .alpha.-amino group
(--NH.sub.2), for example where the amino acid is selected from the
group consisting of Ala, Ser, Thr, Val, Leu, Ile, Pro, Phe, Tyr,
Trp, His, Lys, Arg, .alpha.,.gamma.-diaminobutyric acid (Dab) and
.alpha.,.beta.-diaminopropionic acid (Dap);
[0025] --R.sup.6 together with the carbonyl group and nitrogen
alpha to the carbon to which it is attached is an amino acid
residue;
[0026] --R.sup.7 together with the carbonyl group and nitrogen
alpha to the carbon to which it is attached is an amino acid
residue;
[0027] and --R.sup.6 together with the carbonyl group and nitrogen
alpha to the carbon to which it is attached is not a phenylalanine,
leucine or valine residue and/or --R.sup.7 together with the
carbonyl group and nitrogen alpha to the carbon to which it is
attached is not a leucine, iso-leucine, phenylalanine, threonine,
valine or nor-valine residue;
[0028] R.sup.10 together with the carbonyl group and nitrogen alpha
to the carbon to which it is attached, is a threonine or leucine
residue;
[0029] and salts, solvates, protected forms and/or prodrug forms
thereof.
[0030] In one embodiment, the amino acid at position 6 is
substituted with another amino acid.
[0031] In one embodiment, the amino acid at position 7 is
substituted with another amino acid.
[0032] In one embodiment, where -A.sup.1- is absent, R.sup.T-X-- is
not an .alpha.-amino acid residue, and in particular an
.alpha.-amino acid residue having a free .alpha.-amino group
(--NH.sub.2).
[0033] In one embodiment, where -A.sup.1- is absent, R.sup.T-X-- is
not an an .alpha.-amino acid residue selected from the group
consisting of Ala, Ser, Thr, Val, Leu, Ile, Pro, Phe, Tyr, Trp,
His, Lys, Arg, .alpha.,.gamma.-diaminobutyric acid (Dab) and
.alpha.,.gamma.-diaminopropionic acid (Dap), where the
.alpha.-amino acid has a free .alpha.-amino group (--NH.sub.2).
[0034] In a second aspect of the invention, there is provided a
compound of formula (II), and pharmaceutically acceptable salts and
solvates thereof. The compound of formula (II) is represented
thus:
##STR00004##
[0035] wherein:
[0036] -T.sup.A is hydrogen, C.sub.1-4 alkyl or R.sup.N--X--;
[0037] -A.sup.1- is absent or is an amino acid residue;
[0038] -A.sup.2- is absent or is an amino acid residue;
[0039] -A.sup.3- is absent or is an amino acid residue;
[0040] --X-- is --C(O)--, --NHC(O)--, --OC(O)--, --CH.sub.2-- or
--SO.sub.2--; --R.sup.N is a terminal group, such as a group
--R.sup.T as described herein;
[0041] --R.sup.6A is C.sub.1-12 alkyl, C.sub.0-12 alkyl(C.sub.3-10
cycloalkyl), C.sub.0-12 alkyl(C.sub.3-10 heterocyclyl) or
C.sub.0-12 alkyl(C.sub.5-10 aryl), where the C.sub.1-12 alkyl,
C.sub.3-10 cycloalkyl group C.sub.3-10 heterocyclyl group, and the
C.sub.5-10 aryl group are optionally substituted, and the optional
substituents are as described herein, and with the proviso that
--R.sup.6A is not benzyl, iso-butyl, iso-propyl, and optionally
--R.sup.6A is not methyl, phenyl, 4-hydroxyphenyl, (1H-indol-3-yl)
methyl, 4-phenylphen-1-yl methyl, --(CH.sub.2).sub.7CH.sub.3,
4--(OBn)-phen-1-yl methyl or
--CH.sub.2S(CH.sub.2).sub.5CH.sub.3
[0042] --R.sup.7A together with the carbonyl group and nitrogen
alpha to the carbon to which it is attached is an amino acid
residue;
[0043] R.sup.10 together with the carbonyl group and nitrogen alpha
to the carbon to which it is attached, is a threonine or leucine
residue;
[0044] and salts, solvates, protected forms and/or prodrug forms
thereof.
[0045] In a third aspect the invention provides a pharmaceutical
composition comprising a compound of formula (I) or formula (II)
and a biologically acceptable excipient, optionally together with a
second active agent.
[0046] In a fourth aspect there is provided a compound of formula
(I) or formula (II) or a pharmaceutical composition comprising the
compound of formula (I) or formula (II) for use in a method of
treatment.
[0047] The invention additionally provides a compound of formula
(I) or formula (II) or a pharmaceutical composition comprising the
compound of formula (I) or formula (II) for use in a method of
treating a microbial infection, such as a Gram-negative bacterial
infection.
[0048] The present invention also provides a method of identifying
useful combinations for therapy, the method comprising testing a
combination of a compound of formula (I) or formula (II) with a
biologically active compound and determining the biological
efficacy of the combination, for example with comparison to the
biologically active compound alone and/or the compound of formula
(I) or formula (II).
[0049] In an alternative aspect, the compounds of formula (I) or
formula (II) are suitable for use in the treatment of fungal
infections, for example in combination together with an antifungal
agent.
[0050] In a further aspect of the invention there is provided a
polymyxin compound of formula (I) or formula (II) for use in a
method of treatment or prophylaxis, in combination with an active
agent.
[0051] Also provided are methods for preparing compounds of formula
(I) and formula (II).
[0052] In one aspect of the invention there is provided a compound
of formula (IV):
##STR00005##
[0053] wherein:
[0054] --T.sup.A is hydrogen, C.sub.1-4 alkyl or R.sup.N--X--;
[0055] -A.sup.1- is absent or is an amino acid residue;
[0056] -A.sup.2- is absent or is an amino acid residue;
[0057] -A.sup.3- is absent or is an amino acid residue;
[0058] --X-- is --C(O)--, --NHC(O)--, --OC(O)--, --CH.sub.2-- or
--SO.sub.2--;
[0059] --R.sup.N is a terminal group, such as a group --R.sup.T as
described herein;
[0060] --R.sup.6 together with the carbonyl group and nitrogen
alpha to the carbon to which it is attached is an amino acid
residue;
[0061] --R.sup.7 together with the carbonyl group and nitrogen
alpha to the carbon to which it is attached is an amino acid
residue;
[0062] and one of --R.sup.6 and --R.sup.7 comprises a haloaryl
group, such as a halophenyl group, such as a bromopehnyl group;
[0063] R.sup.10 together with the carbonyl group and nitrogen alpha
to the carbon to which it is attached, is a threonine or leucine
residue;
[0064] and salts, solvates, and/or protected forms thereof.
[0065] In one embodiment, one of one of --R.sup.6 and --R.sup.7
comprises a benzyl group, where the phenyl is substituted with
halo, such as monosubstituted.
[0066] In one embodiment, one of --R.sup.6 and --R.sup.7 comprises
a haloaryl group.
[0067] In one embodiment, one of --R.sup.6 and --R.sup.Z, comprises
a bromoaryl group.
[0068] Other aspects of the invention are discussed in detail
herein.
DETAILED DESCRIPTION OF THE INVENTION
[0069] The present invention provides compounds of formula (I) and
formula (II) for use in medical treatment, particularly in
combination with a second agent.
[0070] Broadly, the compounds of formula (I) and formula (II) are
polymyxin compounds carrying an amino acid substitution within the
polypeptide core. The N terminal of the polymyxin compound is
optionally modified.
[0071] In the compounds of formula (I) the amino acid at position 6
and/or the amino acid at position 7 is substituted with another
amino acid. Thus, the amino acid residue at position 6 and/or
position 7 is not an amino acid residue present in Polymyxin B or
Colistin.
[0072] In the compounds of formula (II) the amino acid at position
6 is substituted with another amino acid, and optionally the amino
acid at position 7 is also substituted. Thus, the amino acid
residue at position 6 and optionally position 7 is not an amino
acid residue present in Polymyxin B or Colistin.
[0073] In both compounds (I) and (II) the amino acids at one or
more of positions 1, 2, 3, and 10 are optionally substituted with
another amino acid. Thus, the amino acid residues at positions 1,
2, 3, and 10 may not be amino acid residues that are present in
Polymyxin B or Colistin. The amino acids at positions 1, 2, and 3
may be optionally deleted.
[0074] The compound of formula (I) is a polymyxin compound having a
modified N terminal. For example, the compound has an N terminal
group that contains one, two or three hydroxyl groups and/or one,
two or three amino groups. In addition to, or as an alternative to,
the N terminal group has a nitrogen-containing heterocyclyl (or
heterocyclylene) group and/or a nitrogen-containing heteroalkylene
group. The N terminal group may be a substituted alkyl group or may
be or include an optionally substituted aryl, cycloalkyl or
heterocyclyl group. The presence of a hydroxyl group or a basic
amino group within the terminal group is associated with particular
advantages, as discussed below.
[0075] The compound of formula (II) is a compound where the N
terminal is optionally modified. Where the N terminal is modified,
the terminal groups may include those fatty acid groups that are
found within the known polymyxin series of compounds, such as
Polymyxin B and Colistin, and other polymyxin compounds reported in
the art, such as those polymyxin derivatives described in WO
2012/168820, WO 2013/072695 and WO 2015/135976.
[0076] The N terminal group within the compounds of formula (II),
where present, may be the same as the N terminal group within the
compounds of formula (I).
[0077] The compounds of formula (I) and formula (II) may have
comparable or improved biological activity compared to Polymyxin B
or Colistin against one or more of E. coli, P. aeruginosa, K.
pneumonia, or A. baumannii bacterial strains. Such compounds are
useful alternatives to the polymyxin type compounds previously
described in the art.
[0078] Furthermore, the present inventors have found that each
compound of formula (I) and formula (II) is active against a broad
range of bacteria. In contrast the compounds previously described
in the art have a varied profile of biological activity.
[0079] Some of the polymyxin compounds or polymyxin derivatives in
the art are known or suspected to have a poor toxicity profile. For
example, the use of compounds having a fatty acyl chain at the N
terminal, such as Polymyxin B and Colistin, is associated with
nephrotoxicity. The use of alternative N terminal group may
therefore reduce toxicity. Thus, the compounds of formula (I)
include hydroxyl and/or amino functionality which the inventors
have shown is associated with a reduction in toxicity, especially a
reduction in nephrotoxicity.
[0080] Vaara et al. (Antimicrob. Agents Chemother. 2008, 52, 3229)
have suggested that the pharmacological and toxicity properties of
a polymyxin compound may be altered with changes to the polymyxin
polypeptide sequence. In particular, Vaara et al. have prepared a
polymyxin compound having only three positive charges, whereas the
polymyxin B nonapeptide carries five positive charges.
[0081] In contrast the present inventors have shown that
adaptations to the N terminal of a polymyxin compound may reduce
nephrotoxicity. As described herein, the N terminal has a
substituent containing a hydroxyl group or an amino group (which
may be in the form of a nitrogen-containing heterocycle).
[0082] Furthermore, the compounds of formula (I) and formula (II)
are believed to be capable of increasing the antimicrobial activity
of a second antimicrobial agent, such as rifampicin. Such
combinations may have comparable or improved biological activity
compared to the combination of the second agent with Polymyxin B or
Colistin, for example against one or more of E. coli, P.
aeruginosa, K. pneumonia, or A. baumannii strains. For example,
compounds of formula (I) and formula (II) may have comparable
biological activity compared to Polymyxin B or Colistin against one
or more of E. coli, P. aeruginosa, K. pneumonia, or A. baumannii
strains.
[0083] Polymyxin Compounds of Formula (I)
[0084] The compounds of formula (I) are variants of Polymyxin B and
are also N-terminal derivatives of the polymyxin series of
compounds. The core of the compound of formula (I) is a variant of
a polymyxin compound, such as a variant of the polymyxin B
decapeptide, nonapeptide (PMBN, Polymyxin 2-10), octapeptide or
heptapeptide, where the amino acid at position 6 and/or position 7
is substituted with another amino acid as described herein, and
optionally the amino acid residues at positions 1, 2, 3 and 10 are
substituted with another amino acid residue. Optionally the amino
acid residue at position 1 (-A.sup.1-) may be deleted.
[0085] Further, the present inventors have also established that
the group attached to the N terminal of a polymyxin nonapeptide is
an important determinant of biological activity and compound
toxicity. The inventors have identified certain N terminal
substituent groups that show enhanced activity and/or exhibit less
toxicity compared to Polymyxin B or Colistin, for example as
measured against HK-2 cells. The activity is associated with the
presence of amino functionality at specific locations within the N
terminal group. Further improvements in activity are also found
where certain substituents are present in the N terminal group, and
the chiral centres in the terminal group have a specific
stereochemistry.
[0086] The inventors' earlier work relating to N terminal groups is
included in the present application for useful support to the
present invention. Whilst the present invention is primarily
focussed on new substitutions at positions 6 and 7 of the polymyxin
core, the variant polypeptide core may be used together with the N
terminal group modifications described in the inventors' earlier
work, such as described in WO 2013/072695, PCT/GB2014/051547
(published as WO 2014/188178) and GB 1404301.2, and most
particularly as described in PCT/GB2014/051547 and in GB
1404301.2.
[0087] The variant polypeptide core may be used together with the N
terminal group modifications described in the inventors' earlier
work, such as described in WO 2015/135976, which claims priority to
GB 1404301.2. Thus, the group --R.sup.15 described in WO
2015/135976 may be used as a group --R.sup.T in the present
case.
[0088] Substitutions and deletions within the polypeptide sequence
of the polymyxin compounds are known.
[0089] For example, the presence of the Dab amino acid residue at
position 1 of Polymyxin B was not believed to be important for
activity, and this amino acid is often absent from polymyxin
derivatives described in the prior art. See, for example, WO
2008/017734 and WO 2009/098357, where the amino acid residue at
position 1 is absent. Similarly, Okimura et al. dispense with the
amino acid residue at position 1, providing instead an
aminocyclohexylcarbonyl substituent at the N terminal of the amino
acid residue at position 2.
[0090] The present inventors have also described polymyxin
nonapeptide forms where the amino acid residue at position 1 is
absent, and the N terminal of the amino acid reside at position 2
is modified. See, for example, WO 2013/072695.
[0091] WO 2012/168820 describes the substitution of the (S)-Dab
amino acid residue at position 3 of Polymyxin B with (S)-Dap. The
authors explain that this substitution provides compounds having
reduced cytotoxicity in human renal cells and improved
antibacterial activity, for example against P. aeruginosa, K.
pneumonia, and/or A. Baumannii.
[0092] WO 2012/168820 suggests that other positions in the
polymyxin polypeptide sequence may be modified, such as at
positions 6 and 7.
[0093] Substitutions and deletions of the amino acids at positions
1, 2 and 3 are also described. The work in WO 2008/017734 and WO
2009/098357 describes the changes in biological activity that are
associated with the changes in the amino acid residues at positions
1, 2 and 3.
[0094] The present invention provides a compound of formula (I) and
the use of this compound in a method of treatment. The compound of
formula (I) is represented thus:
##STR00006##
[0095] wherein:
[0096] --T is R.sup.T--X--;
[0097] -A.sup.1- is absent or is an amino acid residue;
[0098] -A.sup.2- is an amino acid residue selected from threonine
and serine, such as L-threonine and L-serine;
[0099] -A.sup.3- is an amino acid residue represented by:
##STR00007##
[0100] where the asterisk is the point of attachment to -A.sup.2-,
and --R.sup.3 is C.sub.1-6 alkyl, such as C.sub.1-4, having one
amino or one hydroxyl substituent;
[0101] --X-- is --C(O)--, --NHC(O)--, --OC(O)--, --CH.sub.2-- or
--SO.sub.2--;
[0102] --R.sup.T is a terminal group containing hydroxyl and/or
amino functionality, and where -A.sup.1- is absent, R.sup.T--X-- is
not an .alpha.-amino acid residue having a free .alpha.-amino group
(--NH.sub.2), for example where the .alpha.-amino acid residue is
selected from the group consisting of Ala, Ser, Thr, Val, Leu, Ile,
Pro, Phe, Tyr, Trp, His, Lys, Arg, .alpha.,.gamma.-diaminobutyric
acid (Dab) and .alpha.,.beta.-diaminopropionic acid (Dap);
[0103] --R.sup.6 together with the carbonyl group and nitrogen
alpha to the carbon to which it is attached is an amino acid
residue;
[0104] --R.sup.7 together with the carbonyl group and nitrogen
alpha to the carbon to which it is attached is an amino acid
residue;
[0105] and --R.sup.6 together with the carbonyl group and nitrogen
alpha to the carbon to which it is attached is not a phenylalanine,
leucine or valine residue and/or --R.sup.7 together with the
carbonyl group and nitrogen alpha to the carbon to which it is
attached is not a leucine, iso-leucine, phenylalanine, threonine,
valine or nor-valine residue;
[0106] R.sup.10 together with the carbonyl group and nitrogen alpha
to the carbon to which it is attached, is a threonine or leucine
residue;
[0107] and salts, solvates, protected forms and/or prodrug forms
thereof.
[0108] --R.sup.6 and --R.sup.7
[0109] In one embodiment, --R.sup.6 together with the carbonyl
group and nitrogen alpha to the carbon to which it is attached is a
phenylalanine, leucine or valine residue. In this embodiment, the
group --R.sup.7 together with the carbonyl group and nitrogen alpha
to the carbon to which it is attached is not a leucine,
iso-leucine, phenylalanine, threonine, valine or nor-valine
residue.
[0110] In one embodiment, --R.sup.6 together with the carbonyl
group and nitrogen alpha to the carbon to which it is attached is
not a phenylalanine, leucine or valine residue. Additionally or
alternatively, --R.sup.6 together with the carbonyl group and
nitrogen alpha to the carbon to which it is attached is not an
alanine, tyrosine, tryptophan or phenylglycine residue. Thus, the
amino acid residue present at the 6-position may be regarded as a
replacement to the amino acid residues at that position of the
polymyxin core.
[0111] In one embodiment, --R.sup.7 together with the carbonyl
group and nitrogen alpha to the carbon to which it is attached is a
leucine, iso-leucine, phenylalanine, threonine, valine or
nor-valine residue. In this embodiment, --R.sup.6 together with the
carbonyl group and nitrogen alpha to the carbon to which it is
attached is not a phenylalanine, leucine or valine residue.
[0112] In one embodiment, --R.sup.7 together with the carbonyl
group and nitrogen alpha to the carbon to which it is attached, is
an .alpha.-amino acid residue, such as a proteinogenic amino acid
residue, so long as the amino acid residue is not a leucine,
iso-leucine, phenylalanine, threonine, valine or nor-valine
residue.
[0113] In one embodiment, --R.sup.6 together with the carbonyl
group and nitrogen alpha to the carbon to which it is attached, is
an .alpha.-amino acid residue, such as a proteinogenic amino acid
residue, so long as the amino acid residue is not a phenylalanine,
leucine or valine residue.
[0114] In one embodiment, --R.sup.6 together with the carbonyl
group and nitrogen alpha to the carbon to which it is attached, is
an amino acid residue selected from the group consisting of Leu,
OctGly, BipAla, Tyr, norvaline, and norleucine, and for example the
D-forms thereof.
[0115] In one embodiment, --R.sup.7 together with the carbonyl
group and nitrogen alpha to the carbon to which it is attached in
an amino acid residue selected from the group consisting of
leucine, OctGly, BipAla, Cys(S-Hex) and Cys(S-Bzl), and for example
the L-forms thereof. Additionally or alternatively, --R.sup.7
together with the carbonyl group and nitrogen alpha to the carbon
to which it is attached in an amino acid residue selected from the
group consisting of alanine, threonine, serine, valine,
2-aminobutyric acid (Abu) and 2-aminoisobutyric acid (Aib), and for
example the L-forms thereof.
[0116] Alternatively, --R.sup.7 together with the carbonyl group
and nitrogen alpha to the carbon to which it is attached in an
amino acid residue selected from the group consisting of alanine,
phenylalanine, threonine, serine, valine, 2-aminobutyric acid (Abu)
and 2-aminoisobutyric acid (Aib), and for example the L-forms
thereof.
[0117] In one embodiment, --R.sup.7 together with the carbonyl
group and nitrogen alpha to the carbon to which it is attached is a
leucine residue, such as L-leucine. In this embodiment, the amino
acid residue at the 7-position is not substituted with reference to
the amino acid residue at the 7-position of Polymyxin B.
[0118] In one embodiment, the .alpha.-amino acid residue at
position 6 or position 7 is not a proteinogenic amino acid
residue.
[0119] In one embodiment, the .alpha.-amino acid residue does not
contain hydroxyl (--OH) or amino (--NH.sub.2) functionality in its
side chain (i.e. the group --R.sup.6 does not contain a hydroxyl
group or an amino group). Optionally, the .alpha.-amino acid
residue does not contain thiol (--SH) functionality in its side
chain (i.e. the group --R.sup.6 does not contain a thiol
group).
[0120] In one embodiment, the amino acid residue at position 6 is
an L- or D-amino acid residue, such as a D-amino acid residue. In
one embodiment, the amino acid residue at position 7 is an L- or
D-amino acid residue, such as an L-amino acid residue.
[0121] Where position 6 has a D-amino acid residue and position 7
has an L-amino acid residue, the structure of the compound of
formula (I) is:
##STR00008##
[0122] In one embodiment, the compound of formula (I) is the
compound as shown above.
[0123] In one embodiment, a group --R.sup.6 or a group --R.sup.7 is
a group --R.sup.6A as defined below.
[0124] For example, in one embodiment, --R.sup.6 and/or --R.sup.7
is C.sub.1-12 alkyl, C.sub.0-12 alkyl(C.sub.3-10 cycloalkyl),
C.sub.0-12 alkyl (C.sub.3-10 heterocyclyl) or C.sub.0-12
alkyl(C.sub.5-10 aryl), where the C.sub.1-12 alkyl, C.sub.3-10
cycloalkyl group C.sub.3-10 heterocyclyl group, and the C.sub.5-10
carboaryl group are optionally substituted.
[0125] In one embodiment, the group --R.sup.6 is not benzyl,
iso-butyl or iso-propyl (the residue at position 6 may not be
phenylalanine, leucine or valine).
[0126] In one embodiment, the group --R.sup.6 is not
4-phenylphen-1-yl methyl or --CH.sub.2S(CH.sub.2).sub.5CH.sub.3.
The C.sub.1-12 alkyl group, C.sub.3-10 cycloalkyl group, C.sub.3-10
heterocyclyl group, and the C.sub.5-10 aryl group may be
substituted with one or more groups --R.sup.z, where each group
--R.sup.Z is selected from halo, optionally substituted C.sub.1-12
alkyl, optionally substituted C.sub.2-12 alkenyl, optionally
substituted C.sub.2-12 alkynyl, optionally substituted C.sub.3-10
cycloalkyl, optionally substituted C.sub.3-10 heterocyclyl,
optionally substituted C.sub.5-12 aryl, --CN, --NO.sub.2,
--OR.sup.Q, --SR.sup.Q, --N(R.sup.w)C(O)R.sup.Q,
--N(R.sup.Q).sub.2, and --C(O)N(R.sup.Q).sub.2, [0127] where
--R.sup.w is H or C.sub.1-4 alkyl; and [0128] --R.sup.Q is H or
--R.sup.Q1, and --R.sup.Q1 is selected from optionally substituted
C.sub.1-12 alkyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, and
C.sub.5-12 aryl,
[0129] and in a group --N(R.sup.Q).sub.2 the groups --R.sup.Q may
together with the nitrogen atom to which they are attached form a
C.sub.5-6 heterocycle, where the heterocycle is optionally
substituted, [0130] with the proviso that C.sub.1-12 alkyl is not
substituted with alkyl, alkenyl or alkynyl.
[0131] In one embodiment, --R.sup.6 and/or --R.sup.7 is optionally
substituted C.sub.1-12 alkyl.
[0132] In one embodiment, --R.sup.6 and/or --R.sup.7 is optionally
substituted C.sub.1-12 alkyl, where the C.sub.1-12 alkyl is
optionally substituted with one or more groups selected from halo,
such as fluoro, optionally substituted C.sub.3-10 cycloalkyl,
optionally substituted C.sub.3-10 heterocyclyl, optionally
substituted C.sub.5-12 aryl, --CN, --NO.sub.2, --OR.sup.Q,
--SR.sup.Q, --N(R.sup.w)C(O)R.sup.Q, --N(R.sup.Q).sub.2, and
--C(O)N(R.sup.Q).sub.2.
[0133] An alkyl group is typically a C.sub.1-12 alkyl group, such
as C.sub.2-12 alkyl, such as C.sub.4-12 alkyl, such as C.sub.5-12
alkyl, such as C.sub.6-12 alkyl, such as C.sub.8-12 alkyl, for
example C.sub.2-10 alkyl, C.sub.4-10 alkyl, C.sub.5-10 alkyl and
C.sub.6-10 alkyl.
[0134] Additionally or alternatively, an alkyl group may be
C.sub.3-12 alkyl, such as C.sub.3-10 alkyl. The alkyl group may be
linear or branched.
[0135] Where the alkyl group is substituted, it may be
monosubstituted. A substituent may be provided at a terminal of the
alkyl group.
[0136] In one embodiment, --R.sup.6 and/or --R.sup.7 is C.sub.1-12
alkyl substituted with alkylthio or arylalkylthio. Compounds
containing an amino acid residue at position 7 with this
functionality are described by Velkov et al.
[0137] In one embodiment, --R.sup.6 and/or --R.sup.7 is C.sub.1-12
alkyl substituted with alkylthio, such as C.sub.1-12 alkylthio.
[0138] In one embodiment, the alkylthio is C.sub.6 alkylthio.
[0139] In one embodiment, --R.sup.6 and/or --R.sup.7 is
arylalkylthio, such as C.sub.5-10 aryl--C.sub.1-12 alkylthio, such
as phenyl--C.sub.1-12 alkylthio, such as phenyl--C.sub.1-12
alkylthio.
[0140] In one embodiment, the arylalkylthio is benzylthio
(PhCH.sub.2S--).
[0141] In one embodiment, --R.sup.7 is C.sub.3 or C.sub.4
alkyl.
[0142] In one embodiment, --R.sup.7 is n-propyl.
[0143] A C.sub.0-12 alkyl group, such as present in the groups
C.sub.0-12 alkyl(C.sub.3-10 cycloalkyl), C.sub.0-12
alkyl(C.sub.3-10 heterocyclyl) and C.sub.0-12 alkyl(C.sub.5-10
aryl), may be a C.sub.1-12 alkyl group. References to an alkyl
group here are understood to refer to an alkylene linker.
[0144] A C.sub.0-12 alkyl group may be C.sub.1-12 alkyl, such as
C.sub.1-6 alkyl, such as C.sub.1-4 alkyl, such as C.sub.1-2 alkyl,
such as --CH.sub.2-- and --CH.sub.1CH.sub.2--, such as
--CH.sub.2--.
[0145] A C.sub.0-12 alkyl group may be C.sub.1-12 alkyl such as
C.sub.6-12 alkyl, such as C.sub.6-10 alkyl. The C.sub.0-12 alkyl
group may be absent i.e. C.sub.0-12 alkyl group may be C.sub.0.
[0146] In one embodiment, --R.sup.6 and/or --R.sup.7 is C.sub.0-12
alkyl(C.sub.3-10 cycloalkyl), where the C.sub.3-10 cycloalkyl is
optionally substituted.
[0147] The C.sub.3-10 cycloalkyl may be a C.sub.5-7 cycloalkyl
group, such as C.sub.5-6 cycloalkyl group.
[0148] In one embodiment, C.sub.3-10 cycloalkyl is cyclopentyl or
cyclohexyl, such as cyclohexyl.
[0149] A cycloalkyl group may be optionally substituted, such as
optionally monosubstituted.
[0150] Where, the cycloalkyl group is cyclohexyl, the cyclohexyl is
optionally substituted at the 2- or 4-position, such as the
4-position.
[0151] In one embodiment, --R.sup.6 and/or --R.sup.7 is C.sub.1
alkyl(C.sub.6 cycloalkyl). Here, the amino acid residue formed from
--R.sup.6 and/or --R.sup.7 together with the carbonyl group and
nitrogen alpha to the carbon to which it is attached may be
referred to as cyclohexylalanine.
[0152] In one embodiment, --R.sup.7 is cyclohexyl (C.sub.6
cycloalkyl). Here, the amino acid residue formed from --R.sup.7
together with the carbonyl group and nitrogen alpha to the carbon
to which it is attached may be referred to as
cyclohexylglycine.
[0153] In one embodiment, --R.sup.6 is C.sub.1 alkyl(C.sub.6
cycloalkyl).
[0154] In one embodiment, --R.sup.7 is C.sub.1 alkyl(C.sub.6
cycloalkyl).
[0155] In one embodiment, --R.sup.6 and/or --R.sup.7 is not
--(CH.sub.2).sub.4-cycicohexyl.
[0156] In one embodiment, --R.sup.6 and/or --R.sup.7 is not
--(C.sub.6H.sub.10)--Pr, such as where the --Pr group is a linear
propyl group.
[0157] In one embodiment, --R.sup.6 and/or --R.sup.7 is C.sub.0-12
alkyl(C.sub.5-10 aryl), where the C.sub.5-10 aryl is optionally
substituted.
[0158] It is preferred that an aryl group, where present, is a
carboaryl group. The inventors have found that the carboaryl is
associated with an increase antimicrobial effect compared with
heteroaryl functionality.
[0159] In one embodiment, --R.sup.6 and/or --R.sup.7 is substituted
C.sub.0-12 alkyl(C.sub.5-10 aryl).
[0160] In one embodiment, --R.sup.6 and/or --R.sup.7 is substituted
benzyl (--CH.sub.2Ph). The benzyl group may be substituted on the
phenyl ring, such as only on the phenyl ring.
[0161] In one embodiment, --R.sup.6 and/or --R.sup.7 is
monosubstituted benzyl.
[0162] In one embodiment, --R.sup.6 and/or --R.sup.7 is
monosubstituted benzyl, where the phenyl group is substituted at
the 2-, 3- or 4-position, such as the 2- or 4-position, such as the
4-position.
[0163] As noted above, C.sub.1-12 alkyl group, C.sub.3-10
cycloalkyl group, C.sub.3-10 heterocyclyl group, and the C.sub.5-10
aryl group may be substituted with one or more groups --R.sup.z.
Examples of --R.sup.7 include optionally substituted alkyl,
alkenyl, alkynyl, cycloalkyl, aryl and heterocycle groups.
[0164] Where a group, such as alkyl, alkenyl, alkynyl, cycloalkyl,
aryl and heterocycle, is optionally substituted, the group may have
one or more substituent groups selected from halo, haloalkyl,
alkyl, alkenyl, alkynyl, and aryl, except that alkyl alkenyl, and
alkynyl groups are not substituents to the alkyl alkenyl, and
alkynyl groups.
[0165] The optional substituents may include groups such as -13
OR.sup.Q, --SR.sup.Q, --N(R.sup.w)C(O)R.sup.Q, --N(R.sup.Q).sub.2,
and --C(O)N(R.sup.Q).sub.2.
[0166] In one embodiment, each --R.sup.Q is --R.sup.Q1. Thus,
hydroxyl (--OH) and primary amino functionality (--NH.sub.2) is not
present.
[0167] An aryl group may be a carboaryl group, such as C.sub.6-10
carboaryl, or a heteroaryl group, such as C.sub.5-10
heteroaryl.
[0168] In one embodiment, a reference to aryl is a reference to
phenyl.
[0169] A haloalkyl group is an alkyl group, such as described
above, having one or more halo substituents. The haloalkyl group
may be a perhaloalkyl group. In one embodiment, a haloalkyl group
is --CF.sub.3.
[0170] An alkenyl group is typically a C.sub.2-12 alkenyl, such as
C.sub.4-12 alkenyl, such as C.sub.5-12 alkenyl, such as C.sub.6-12
alkenyl, for example C.sub.2-10 alkenyl, C.sub.4-10 alkenyl,
C.sub.6-10 alkenyl and C.sub.6-10 alkenyl.
[0171] An alkynyl group is typically a C.sub.2-12 alkynyl, such as
C.sub.4-12 alkynyl, such as C.sub.6-12 alkynyl, such as C.sub.6-12
alkynyl, for example C.sub.2-10 alkynyl, C.sub.4-10 alkynyl,
C.sub.5-10 alkynyl and C.sub.6-10 alkynyl.
[0172] An alkyl, alkenyl or alkynyl group may be a linear or
branched group.
[0173] In one embodiment, the alkyl, alkenyl or alkynyl group is
unsubstituted.
[0174] A cycloalkyl group is typically C.sub.3-10 cycloalkyl may be
a C.sub.5-7 cycloalkyl group, such as C.sub.5-6 cycloalkyl
group.
[0175] In one embodiment, C.sub.3-10 cycloalkyl is cyclopentyl or
cyclohexyl, such as cyclohexyl.
[0176] A group --R.sup.Z may be halo, such as bromo.
[0177] A group --R.sup.Z may be alkyl, such as C.sub.1-12 alkyl,
such as C.sub.2-12 alkyl, such as C.sub.4-12 alkyl, such as
C.sub.5-12 alkyl, such as C.sub.6-12 alkyl, for example C.sub.2-10
alkyl, C.sub.4-10 alkyl, C.sub.5-10 alkyl and C.sub.6-10 alkyl.
[0178] The alkyl group may be a linear or branched alkyl group.
[0179] A group --R.sup.Z may be aryl, such as carboaryl, such as
C.sub.6-10 carboaryl, or heteroaryl, such as C.sub.5-10 heteroaryl.
A group --R.sup.Z may be phenyl. The aryl group may be substituted
with one or more, such as one, substituent groups. In one
embodiment, the aryl group is substituted with halo, haloalkyl,
alkyl and aryl.
[0180] In one embodiment, --R.sup.6 and/or --R.sup.7 is benzyl,
where the phenyl group is substituted at the 2- or 4-postion, such
as the 4-position, with phenyl (i.e. forming a biphenyl group).
[0181] In one embodiment, --R.sup.6 and/or --R.sup.7 is benzyl,
where the phenyl group is substituted at the 2- or 4-postion, such
as the 4-postion, with alkyl, such as C.sub.1-12 alkyl.
[0182] In one embodiment, --R.sup.6 and/or --R.sup.7 is benzyl,
where the phenyl group is substituted at the 2-, 3- or 4-postion,
such as the 2- or 4-postion, such as the 4-position, with halo,
such as bromo. In one embodiment, --R.sup.6 and/or --R.sup.7 is
benzyl, where the phenyl group is substituted at the 2- or
4-postion, such as the 4-postion, with cycloalkyl, such as C.sub.6
cycloalkyl.
[0183] In one embodiment, --R.sup.6 and/or --R.sup.7 is not
4-hydroxyphenylmethyl (i.e. --R.sup.6 together with the carbonyl
group and nitrogen alpha to the carbon to which it is attached is
not a tyrosine residue).
[0184] The comments above refer to compounds where the a amino acid
residue at position 6 or position 7 has an .alpha. carbon atom that
is substituted with --R.sup.6 and --H, or --R.sup.7 and --H. The
--H may also be a site for substitution, providing di-substituted
.alpha. amino acid residues at position 6 and/or position 7.
[0185] In an alternative embodiment, the .alpha. carbon atom within
the .alpha. amino acid residue at position 6 and/or position 7 is
di-substituted, where each substituent is a group --R.sup.6 or
--R.sup.7 as described herein.
[0186] In an alternative embodiment, the a carbon atom within the a
amino acid residue at position 6 and/or 7 is di-substituted, where
each substituent is a group --R.sup.6 or --R.sup.7 as appropriate,
where the groups --R.sup.6 may together with the a carbon atom to
which they are attached form a C.sub.4-6 carbocycle or a C.sub.5-6
heterocycle, and/or the groups --R.sup.7 may together with the
.alpha. carbon atom to which they are attached form a C.sub.4-6
carbocycle or a C.sub.5-6 heterocycle, wherein the carbocycle and
the heterocycle are optionally substituted with one or more groups
--R.sup.z, as described above. The carbocycle is a cycloalkyl group
as described herein. The heterocycle is a heterocyclyl group as
described herein.
[0187] Where a heterocycle is present the heteroatom of the
heterocyclyl group is not provided at the .beta. position (i.e. the
heteroatom is not connected to the .alpha. carbon).
[0188] The heterocycle contains a heteroatom selected from N, O and
S, and optionally contains further heteroatoms. A reference to N is
a reference to a group --NH-- within a heterocycle, and a reference
to S is --S--, --S(O)-- or --S(O).sub.2--.
[0189] In one embodiment, --R.sup.6 and/or --R.sup.7 together with
the carbonyl group and nitrogen alpha to the carbon to which it is
attached is an amino having a piperidine side chain that is a gem
di-substituent to the .alpha.-carbon. Thus the .alpha.-carbon is a
ring atom in the piperidine ring. This is a cyclic analogue of
Dab.
[0190] --R.sup.10
[0191] The --R.sup.10 position corresponds to amino acid position
10 in the polymyxin compounds. In one embodiment --R.sup.10
together with the carbonyl group and nitrogen alpha to the carbon
to which it is attached is a threonine residue, such as
L-threonine.
[0192] -A.sup.1-, -A.sup.2- and -A.sup.3-
[0193] In one embodiment, -A.sup.1- is absent, and -A.sup.2- and
-A.sup.3- are present. Such a compound may be referred to as a
nonapeptide. Nonapeptide forms of Polymyxin B and E are well known
in the art.
[0194] In one embodiment, -A.sup.1-, -A.sup.2- and -A.sup.3- are
present. Such a compound may be referred to as a decapeptide, and
are based on, for example, deacylated decapeptide forms of
Polymyxin B, E and M. Deacylated forms of Polymyxin B, E and M are
well known in the art. Alternative decapeptides may be prepared
from a nonapeptide or heptapeptide by appropriate coupling of an
amino acid/s to the N terminal of the nonapeptide or heptapeptide.
It is noted that the deacylated form Polymyxin M would appear to be
identical to that reported for Polymyxin A by Cubist (see WO
2010/075416 and U.S. Pat. No. 8,415,307).
[0195] It is noted that the compounds of the invention differ from
Polymyxin B, E and M, and their deacylated forms, for at least the
reason that the amino acid residue at position 6 and/or position 7
differs from the amino acid residue present in Polymyxin B, E and
M.
[0196] The compounds of the invention, such as the compounds of
formula (I) may also differ from Polymyxin B, E and M in the nature
of the N terminal group. Polymyxins B, E and M have an fatty acid
(fatty acyl) group at the N terminal. In contrast, the compounds of
formula (I) have a terminal group with hydroxyl and/or amino
functionality.
[0197] The group -A.sup.1- may be an .alpha.-amino acid.
[0198] A reference to an .alpha.-amino acid includes proteinogenic
("natural") .alpha.-amino acids, optionally together with other
.alpha.-amino acids.
[0199] Examples of .alpha.-amino acids that are not proteinogenic
are those amino acids generated by post-translational modification,
or by other means. Examples include Dab, Dap, Dgp
(.alpha.,.beta.-diguanidinopropanoyl), ornithine and nor-valine
[0200] Also included are amino having a piperidine side chain that
is a gem di-substituent to the .alpha.-carbon. Thus the
.alpha.-carbon is a ring atom in the piperidine ring. This is a
cyclic analogue of Dab.
[0201] In one embodiment, -A.sup.1- is an amino acid residue.
[0202] In one embodiment, -A.sup.1- is an .alpha.-amino acid
residue.
[0203] In one embodiment, -A.sup.1- is an amino acid selected from
the group consisting of Lys, Arg, Dap, Ser, Thr, Ile, Tyr, His,
Phe, Pro, Trp, Leu, Ala, Dab, Dap, Dgp
(.alpha.,.beta.-diguanidinopropanoyl), ornithine and nor-valine,
including L- and D-forms thereof.
[0204] In one embodiment, -A.sup.1- is an amino acid selected from
the group consisting of Dab, Pro, Dap, Gly, Ser, His, Phe, Arg,
Tyr, and Leu, including L- and D-forms thereof.
[0205] In one embodiment, -A.sup.1- is a D .alpha.-amino acid.
[0206] In one embodiment, -A.sup.1- is an L .alpha.-amino acid.
[0207] In one embodiment, -A.sup.1- is a .beta.-amino acid.
[0208] The compounds of the invention where -A.sup.1- is an amino
acid may be prepared from deacylated forms by appropriate
derivatisation of the N terminal.
[0209] In one embodiment, -A.sup.1- is selected from Lys, Arg, Dap,
Ser, Phe, Trp, Leu, Ala, Dab, Dap, ornithine or nor-valine,
including L- and D-forms thereof.
[0210] In one embodiment, -A.sup.1- is selected from Thr, Ser, Lys,
Dab or Dap, for example L-Thr, L-Ser, L-Lys, L-Dab or L-Dap.
[0211] In one embodiment, -A.sup.1- is Dab, such as L-Dab.
[0212] In an alternative embodiment, where -A.sup.1- is an amino
acid it is not Dab, for example it is not L-Dab.
[0213] In one embodiment, -A.sup.2- is an amino acid residue
selected from threonine and serine, such as L-threonine and
L-serine.
[0214] In one embodiment, -A.sup.3- is an amino acid residue
represented by:
##STR00009##
[0215] where the asterisk is the point of attachment to -A.sup.2-,
and --R.sup.3 is C.sub.1-6 alkyl, such as C.sub.1-4 alkyl, having
one amino or one hydroxyl substituent. The amino acid residue may
be an L-form.
[0216] In one embodiment, --R.sup.3 has one amino substituent.
[0217] In one embodiment, --R.sup.3 has one hydroxyl
substituent.
[0218] The amino group may be --NH.sub.2, --NHMe or --NHEt. In one
embodiment, the amino group is --NH.sub.2.
[0219] In one embodiment, --R.sup.3 together with the carbonyl
group and nitrogen alpha to the carbon to which it is attached, is
.alpha.,.gamma.-diaminobutyric acid (Dab), a serine residue, a
threonine residue, a lysine residue, an ornithine residue, or
.alpha.,.beta.-diaminopropionic acid (Dap).
[0220] In one embodiment, --R.sup.3 together with the carbonyl
group and nitrogen alpha to the carbon to which it is attached, is
.alpha.,.gamma.-diaminobutyric acid (Dab), a serine residue, a
lysine residue, or .alpha.,.beta.-diaminopropionic acid (Dap).
[0221] In one embodiment, --R.sup.3 together with the carbonyl
group and nitrogen alpha to the carbon to which it is attached, is
.alpha.,.gamma.-diaminobutyric acid (Dab) or
.alpha.,.beta.-diaminopropionic acid (Dap), such as L-Dab or
L-Dap.
[0222] In one embodiment, --R.sup.3 together with the carbonyl
group and nitrogen alpha to the carbon to which it is attached, is
.alpha.,.gamma.-diaminobutyric acid (Dab) or
.alpha.,.beta.-diaminopropionic acid (Dap), such as L-Dab or
L-Dap.
[0223] In one embodiment, --R.sup.3 together with the carbonyl
group and nitrogen alpha to the carbon to which it is attached, is
a lysine residue, such as L-Lys.
[0224] In one embodiment, --R.sup.3 together with the carbonyl
group and nitrogen alpha to the carbon to which it is attached, is
Dab, such as L-Dab.
[0225] Compounds of the invention where --R.sup.3 is a Dab side
chain are obtainable from compounds such as Polymyxin B. Compounds
where --R.sup.3 is a Dap side chain may be prepared using the
methods described in WO 2012/168820. Compounds where --R.sup.3 is a
serine side chain may be prepared using the methods described by
Vaara et al. (see, for example, Antimicrob. Agents Chemother. 2008,
52, 3229).
[0226] --X--
[0227] The group --X-- may be selected from --NHC(O)--, --C(O)--,
--OC(O)--, --CH.sub.2-- and --SO.sub.2--.
[0228] In one embodiment --X-- is selected from --C(O)--,
--SO.sub.2-- and --CH.sub.2--.
[0229] In one embodiment --X-- is --C(O)--.
[0230] In one embodiment --X-- is --SO.sub.2--.
[0231] In one embodiment --X-- is --CH.sub.2--.
[0232] The right-hand side of the group --X-- is the point of
attachment to NH, the amino terminal of an amino acid residue, such
as -A.sup.1-, -A.sup.2- or -A.sup.3-. The left-hand side of the
group --X-- is the point of attachment to a group such as --R.sup.T
(or --R.sup.N for the compounds of formula (II).
[0233] --R.sup.7
[0234] The group --R.sup.T together with --X-- is an N terminal
modification of the polymyxin. The group --R.sup.T contains
hydroxyl and/or amino functionality.
[0235] In one embodiment, R.sup.T--X-- is not an .alpha.-amino acid
residue, and specifically R.sup.T--X-- is not an .alpha.-amino acid
residue having a free amine N terminal i.e. a group --NH.sub.2 that
is attached to the a carbon of the amino acid residue. For example,
R.sup.T--X-- is not an .alpha.-amino acid residue when -A.sup.1- is
absent. In one embodiment, R.sup.T--X-- is not an .alpha.-amino
acid residue when -A.sup.1- is present. The amino acid may be
selected from the group consisting of Ala, Ser, Thr, Val, Leu, Ile,
Pro, Phe, Tyr, Trp, His, Lys, Arg, .alpha.,.gamma.-diaminobutyric
acid (Dab) and .alpha.,.beta.-diaminopropionic acid (Dap).
[0236] The group --R.sup.T may contain one, two or three hydroxyl
groups, --OH.
[0237] The group --R.sup.T may contain one, two or three amino
groups, --NR.sub.A-R.sup.B, where each --R.sup.A is independently
hydrogen or C.sub.1-4 alkyl, each --R.sup.B is independently
hydrogen or C.sub.1-4 alkyl, or --NR.sup.A-R.sup.B is a guanidine
group.
[0238] The group --R.sup.T may contain one, two or three amino
groups, where such amino groups are present within a
nitrogen-containing heterocycle, such as azetidine, pyrrolidinyl,
piperidinyl, piperazinyl or morpholinyl, or a nitrogen-containing
heteroalkyl group.
[0239] The group --R.sup.T may contain both hydroxyl and amino
functionality.
[0240] In one embodiment, --R.sup.T is not amino-substituted
cyclohexyl, for example when --X-- is --C(O)--.
[0241] The compounds of formula (I) do not encompass the deacylated
versions of Polymyxin B (Deacylpolymyxin B-DAPB), D, E
(Deacylcolistin-DAC) or M, or Circulin A. The compounds of formula
(I) do not encompass the nonapeptide versions of Polymyxin B
(PMBN), D, E or M, or Circulin A.
[0242] In one embodiment, R.sup.T--X-- is not an .alpha.-amino acid
residue. An .alpha.-amino acid residue is a group where --X-- is
--C(O)-- and --R.sup.T has a group --NR.sup.AR.sup.B (such as
--NH.sub.2) as a substituent to the carbon atom that is a to the
group --X--.
[0243] A reference to an .alpha.-amino acid may be a reference to a
proteinogenic ("natural") .alpha.-amino acid, optionally together
with other .alpha.-amino acids.
[0244] Examples of .alpha.-amino acids that are not proteinogenic
are those amino acids generated by post-translational modification,
or by other means. Examples include Dab, Dap, Dgp
(.alpha.,.beta.-diguanidinopropanoyl), ornithine and
nor-valine.
[0245] In one embodiment, R.sup.T--X-- is not Thr, Ser,
.alpha.,.gamma.-diaminobutyric acid (Dab) or
.alpha.,.beta.-diaminopropionic acid (Dap) residues.
[0246] In one embodiment, for example where the core of the
compound of formula (I) is Polymyxin B, R.sup.T--X-- is not a Lys,
Arg, Dap, Ser, Phe, Trp, Leu or Ala residue. In one embodiment,
R.sup.T--X-- is not a Lys, Arg, Dap, Ser, Phe, Trp, Leu, Ala, Glu,
.alpha.,.gamma.-diaminobutyric acid (Dab) or
.alpha.,.beta.-diaminopropionic acid (Dap) residue.
[0247] In one embodiment, R.sup.T--X-- is not an Ala, Ser, Thr,
Val, Leu, Ile, Pro, Phe, Tyr, Trp, His, Lys, Glu, or Arg
residue.
[0248] In one embodiment, R.sup.T--X-- is not an Ala, Ser, Thr,
Val, Leu, Ile, Pro, Phe, Tyr, Trp, His, Lys, Glu, Arg,
.alpha.,.gamma.-diaminobutyric acid (Dab) or
.alpha.,.beta.-diaminopropionic acid (Dap) residue.
[0249] In one embodiment, R.sup.T--X-- is not a proteinogenic
("natural") .alpha.-amino acid residue or a
.alpha.,.gamma.-diaminobutyric acid (Dab) or
.alpha.,.beta.-diaminopropionic acid (Dap) residue.
[0250] References to the amino acids above, may be a reference to
the L- or D-form, such as the L-form.
[0251] In one embodiment, --R.sup.T is not diaminophenyl, such as
3,5-diaminophenyl, for example when --X-- is --C(O)--.
[0252] Examples of --R.sup.T
[0253] The present inventors have previously described the
modification of the N terminal group of polymyxin nonapeptide
compounds, such as N terminal modifications to PMBN.
[0254] This work is described in WO 2013/072695, the contents of
which are hereby incorporated by reference in their entirety.
[0255] The group --R.sup.T may be additionally or alternatively
selected from the N terminal groups of PCT/GB2014/051547 and/or GB
1404301.2, the contents of which are hereby incorporated by
reference in their entirety.
[0256] In one embodiment, --R.sup.T is not a group selected from
the terminal groups of WO 2013/072695.
[0257] Terminal Groups of WO 2013/072695
[0258] The terminal group --R.sup.T in the present case may be a
group --R.sup.5 as described in WO 2013/072695.
[0259] Thus, in one embodiment, and for example where -A.sup.1- is
absent, --R.sup.T is selected from the group consisting of
C.sub.0-12 alkyl(C.sub.4-6 nitrogen heterocyclyl), or C.sub.2-12
alkyl or C.sub.0-12 alkyl(C.sub.3-8 cycloalkyl) wherein the alkyl
or cycloalkyl bears (i) one, two or three hydroxyl groups; or (ii)
one --NR.sup.AR.sup.B group; or (iii) one --NR.sup.AR.sup.B group
and one or two hydroxyl groups. In one embodiment, --R.sup.T is not
a group selected from this list, for example where -A.sup.1- is
absent.
[0260] The C.sub.0-12 alkyl group is an alkylene spacer linking the
nitrogen heterocyclyl or cycloalkyl to --X--.
[0261] The spacer may be absent (this is C.sub.0).
[0262] The C.sub.0-12 alkyl group may be C.sub.0-6 alkyl or
C.sub.0-4 alkyl, or C.sub.1-12 alkyl, such as C.sub.1-6, such as
C.sub.1-4 alkyl. The alkyl group may be linear or branched, such as
linear.
[0263] In one embodiment, --R.sup.T is C.sub.0-12 alkyl(C.sub.4-6
nitrogen heterocyclyl).
[0264] The C.sub.4-6 nitrogen heterocyclyl is a saturated
carbocyclic ring comprising at least one nitrogen ring atom, for
example 1 or 2 nitrogen ring atoms, such as only 1 nitrogen ring
atom and optionally containing a further ring heteroatom selected
from oxygen and sulfur.
[0265] Examples of C.sub.4-6 heterocyclyl groups include azetidine,
pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, such as
azetidine, pyrrolidinyl and piperidinyl.
[0266] In one embodiment the heterocyclyl is linked to the
remainder of the molecule through nitrogen. In the term "C.sub.4-6
heterocyclyl", the expression C.sub.4-6 represents the total number
of ring atoms, including carbon and heteroatoms.
[0267] In one embodiment, --R.sup.T is C.sub.2-12 alkyl or
C.sub.0-12 alkyl(C.sub.3-8 cycloalkyl) wherein the alkyl or
cycloalkyl bears (i) one, two or three hydroxyl groups; or (ii) one
--NR.sup.AR.sup.B group; or (iii) one --NR.sup.AR.sup.B group and
one or two hydroxyl groups.
[0268] In one embodiment, --R.sup.T is C.sub.2-12 alkyl,
substituted as described above.
[0269] The C.sub.2-12 alkyl group may be C.sub.3-12 alkyl,
C.sub.4-12 alkyl, C.sub.5-12 alkyl or C.sub.6-12 alkyl.
[0270] In one embodiment, --R.sup.T is C.sub.0-12 alkyl(C.sub.3-8
cycloalkyl) substituted as described above.
[0271] The C.sub.3-8 cycloalkyl group may be C.sub.3-6 cycloalkyl
such as C.sub.5-6, for example C5 cycloalkyl or C.sub.6
cycloalkyl.
[0272] In one embodiment --R.sup.T bears one substituent.
[0273] In one embodiment --R.sup.T bears two substituents.
[0274] In one embodiment --R.sup.T bears three substituents.
[0275] In one embodiment --R.sup.T bears one, two or three hydroxyl
groups, for example one hydroxyl group.
[0276] In one embodiment --R.sup.T bears one amine group, for
example a C.sub.2-12 alkyl bearing one amine, such as C.sub.2-4
alkyl bearing one amine.
[0277] In one embodiment --R.sup.T bears one, two or three hydroxyl
groups, such as one hydroxyl.
[0278] In one embodiment --R.sup.T bears one amine group and one
hydroxyl group.
[0279] In one embodiment --R.sup.T bears one amine group and two
hydroxyl groups.
[0280] In one embodiment wherein --R.sup.T bears one or more
hydroxyls then the alkyl chain is C.sub.5-12.
[0281] In one embodiment --R.sup.T does not bear more than one
amine group.
[0282] In one embodiment wherein --R.sup.T bears more than one
substituent, the substituents are not located on the same carbon
atom.
[0283] In one embodiment at least one --R.sup.T substituent (such
as one substituent) is on a terminal carbon of a straight alkyl
chain or an alkyl branch, for example a straight alkyl chain.
Terminal carbon as employed herein is intended to refer to carbon
that would be --CH.sub.3 if it bore no substituents.
[0284] In one embodiment, the group --R.sup.T is not a group as
described above.
[0285] --R.sup.A and --R.sup.B
[0286] In one embodiment, --R.sup.A is hydrogen.
[0287] In one embodiment, --R.sup.A is C.sub.1-4 alkyl, such as
methyl, ethyl or propyl, such as methyl.
[0288] In one embodiment, --R.sup.B is hydrogen.
[0289] In one embodiment, --R.sup.B is C.sub.1-4 alkyl, such as
methyl, ethyl or propyl, such as methyl.
[0290] In one embodiment, --R.sup.A is not ethyl when --R.sup.B is
hydrogen, methyl or ethyl.
[0291] In one embodiment, --R.sup.A is not methyl when --R.sup.B is
hydrogen, methyl or ethyl.
[0292] In one embodiment, --R.sup.A is hydrogen and --R.sup.B is
hydrogen.
[0293] In one embodiment, --NR.sup.AR.sup.B is not a guanidine
group.
[0294] Terminal Groups of PCT/GB2014/051547 (WO 2014/188178)
[0295] The inventors have established that additional compounds
having modified terminal groups may have biological activity. These
additional compounds are described in PCT/GB2014/051547 (now
published as WO 2014/188178). There terminal groups are not
described in WO 2013/072695.
[0296] The terminal group --R.sup.T in the present case may be a
group --R.sup.5 as described in PCT/GB2014/051547 for the compounds
of formula (IIa), (IIb), (IIc), (IId), (IIe), (IIf) and (IIg).
[0297] Thus, in one embodiment, --R.sup.T is a group
G-L.sup.2-L.sup.1-, and --G is C.sub.5-12 aryl, [0298] --L.sup.1--
is a covalent bond, C.sub.1-12 alkylene or C.sub.2-12
heteroalkylene, [0299] --L.sup.2-- is a covalent bond or C.sub.4-10
heterocyclylene, [0300] --R.sup.T is substituted with: [0301] (i)
one, two or three hydroxyl groups, or [0302] (ii) one, two or three
groups --NR.sup.AR.sup.B, or [0303] (iii) one or two groups
--NR.sup.AR.sup.B, and one, two or three hydroxyl groups,
[0304] with the proviso that (i), (ii) and (iii) are optional
substituents when --L.sup.1-- is a nitrogen-containing C.sub.2-12
heteroalkylene and/or --L.sup.2-- is a nitrogen-containing
C.sub.4-10 heterocyclylene, [0305] and the aryl group is optionally
substituted.
[0306] In one embodiment, --R.sup.T is a group G-L.sup.2-L.sup.1-,
and --G is C.sub.3-10 cycloalkyl, [0307] --L.sup.1-- is a covalent
bond, C.sub.1-12 alkylene or C.sub.2-10 heteroalkylene, [0308]
--L.sup.2-- is a covalent bond or C.sub.4-12 heterocyclylene,
[0309] with the proviso that --L.sup.2-- is a covalent bond only
when --L.sup.1-- is C.sub.2-10 heteroalkylene, [0310] --R.sup.T is
substituted with: [0311] (i) one, two or three hydroxyl groups, or
[0312] (ii) one, two or three groups --NR.sup.AR.sup.B, or [0313]
(iii) one or two groups --NR.sup.AR.sup.B, and one, two or three
hydroxyl groups, with the proviso that (i), (ii) and (iii) are
optional substituents when --L.sup.1-- is a nitrogen-containing
C.sub.2-12 heteroalkylene and/or --L.sup.2-- is a
nitrogen-containing C.sub.4-10 heterocyclylene, [0314] and
optionally the cycloalkyl group is independently optionally
substituted.
[0315] In one embodiment, --R.sup.T is G-L.sup.2-L.sup.1--, where
--G is C.sub.3-10 cycloalkyl or C.sub.2-12 alkyl, [0316]
--L.sup.1-- is a covalent bond or C.sub.1-12 alkylene, [0317]
--L.sup.2-- is a covalent bond,
[0318] with the proviso that --L.sup.1-- is not C.sub.1-12 alkylene
when --G is C.sub.2-12 alkyl, [0319] --R.sup.T is substituted with:
[0320] (i) two or three groups --NR.sup.AR.sup.B, or [0321] (ii)
two groups --NR.sup.AR.sup.B, and one, two or three hydroxyl
groups; [0322] and the alkyl or cycloalkyl group is independently
optionally substituted.
[0323] In one embodiment, --R.sup.T is D-L.sup.1--, where
D-L.sup.1-- is substituted with: [0324] (i) one, two or three
hydroxyl groups, or [0325] (ii) one, two or three groups
--NR.sup.AR.sup.B, or [0326] (iii) one or two groups
--NR.sup.AR.sup.B, and one, two or three hydroxyl groups; [0327]
--D is C.sub.4-10 heterocyclyl; [0328] --L.sup.1-- is a covalent
bond, C.sub.1-12 alkylene or C.sub.2-12 heteroalkylene,
[0329] with the proviso that (i), (ii) and (iii) are optional
substituents when --L.sup.1-- is a nitrogen-containing C.sub.2-12
heteroalkylene,
[0330] and the heterocyclyl group is independently optionally
substituted.
[0331] In one embodiment, where -A.sup.1-, -A.sup.2- and -A.sup.3-
are present, --R.sup.T is --R.sup.P.
[0332] In one embodiment, where -A.sup.1- is absent, and -A.sup.2-
and -A.sup.3- are present, --R.sup.T is --R.sup.P, with the proviso
--X-- and --R.sup.T together are not an L-.alpha.-amino acid
residue, such as --X-- and --R.sup.T together are not L-Lys, L-Arg,
L-Dap, L-Ser, L-Dab, L-Dgp (L-.alpha.,.beta.-diguanidinopropanoyl)
or L-Abu.
[0333] The group --R.sup.P is as described below.
[0334] Where an aryl group is present in --R.sup.T it is
independently optionally substituted one or more substituents
selected from --C.sub.1-10 alkyl, such as --C.sub.1-4 alkyl, halo,
--CN, --NO.sub.2, --CF.sub.3, --NR.sup.10C(O)R.sup.10, --OCF.sub.3,
--CON(R.sup.10).sub.2, --COOR.sup.9, --OCOR.sup.10,
--NR.sup.10COOR.sup.10, --OCON(R.sup.10).sub.2,
--NR.sup.10CON(R.sup.10).sub.2, --OR.sup.9, --SR.sup.9,
--NR.sup.10SO.sub.2R.sup.10, --SO.sub.2N(R.sup.10)2 and
--SO.sub.2R.sup.10 where each --R.sup.9 is independently
--C.sub.1-10 alkyl, such as --C.sub.1-4 alkyl and each --R.sup.10
is independently --H or --C.sub.1-10 alkyl, such as --C.sub.1-4
alkyl.
[0335] Where an alkyl, cycloalkyl, or heterocyclyl group is present
in --R.sup.T it is independently optionally substituted one or more
substituents selected from --C.sub.1-10 alkyl, such as --C.sub.1-4
alkyl, halo, --CN, --NO.sub.2, --CF.sub.3, --C(O)R.sup.10,
--NR.sup.10C(O)R.sup.10, --OCF.sub.3, --CON(R.sup.10).sub.2,
--COOR.sup.9, --OCOR.sup.10, --NR.sup.10COOR.sup.10,
--OCON(R.sup.10).sub.2, --NR.sup.10CON(R.sup.10).sub.2, --OR.sup.9,
--SR.sup.9, --NR.sup.10SO.sub.2R.sup.10,
--SO.sub.2N(R.sup.10).sub.2 and --SO.sub.2R.sup.10 where each
--R.sup.9 is independently --C.sub.1-10 alkyl, such as --C.sub.1-4
alkyl and each --R.sup.10 is independently --H or --C.sub.1-10
alkyl, such as --C.sub.1-4 alkyl, except that alkyl is not
substituted with alkyl.
[0336] --R.sup.P
[0337] The group --R.sup.P is G-L.sup.2-L.sup.1--, where [0338] --G
is selected from: [0339] C.sub.2-12 alkyl, [0340] C.sub.5-12 aryl,
[0341] C.sub.3-10 cycloalkyl, [0342] --L.sup.1-- is a covalent
bond, C.sub.1-12 alkylene or C.sub.2-12 heteroalkylene, [0343]
--L.sup.2-- is a covalent bond or C.sub.4-10 heterocyclylene,
[0344] with the proviso that --L.sup.1-- is not C.sub.1-12 alkylene
when --G is C.sub.2-12 alkyl, and G-L.sup.2-L.sup.1-- is
substituted with: [0345] (i) one, two or three hydroxyl groups, or
[0346] (ii) one, two or three groups --NR.sup.AR.sup.B, or [0347]
(iii) one or two groups --NR.sup.AR.sup.B, and one, two or three
hydroxyl groups, with the proviso that (i), (ii) and (iii) are
optional substituents when --L.sup.1-- is a nitrogen-containing
C.sub.2-12 heteroalkylene and/or --L.sup.2-- is a
nitrogen-containing C.sub.4-10 heterocyclylene,
[0348] or --R.sup.P is D-L.sup.1--, where --D is C.sub.4-10
heterocyclyl and --L.sup.1-- is as defined above, and D-L.sup.1--
is substituted with: [0349] (i) one, two or three hydroxyl groups,
or [0350] (ii) one, two or three groups --NR.sup.AR.sup.B, or
[0351] (iii) one or two groups --NR.sup.AR.sup.B, and one, two or
three hydroxyl groups, [0352] with the proviso that (i), (ii) and
(iii) are optional substituents when --L.sup.1-- is a
nitrogen-containing C.sub.2-12 heteroalkylene and/or --D is a
nitrogen-containing C.sub.4-10 heterocyclyl.
[0353] The optional substituents may be optional substituents as
described above.
[0354] In one embodiment, --X-- and --R.sup.P together are not an
L-.alpha.-amino acid, such as Lys, Arg, Dap, Ser, Phe, Trp, Leu,
Ala, .alpha.,.gamma.-diaminobutyric acid (Dab) or
.alpha.,.beta.-diaminopropionic acid (Dap), optionally together
with Dgp and Abu.
[0355] Terminal Groups of GB 1404301.2 and WO 2015/135976
[0356] In the polymyxins, the amino acid residue at position 1 is a
diamino butyric acid (Dab) residue which is acylated at its
N-terminal with a fatty acyl chain. Within the compounds described
in GB 1404301.2, the N-terminal group of Polymyxin comprising Dab
and the fatty acyl chain is replaced by an amine-containing moiety
which is linked to a further substituent, but not linked via an
amide bond. WO 2015/135976 claims priority to GB 1404301.2.
[0357] The N terminal groups described in GB 1404301.2 may be used
in the present case. The terminal group --R.sup.T in the present
case may be a group --R.sup.15 as described in GB 1404301.2 for the
compounds of formula (III). Additionally or alternatively the N
terminal groups described in WO 2015/135976 may be used in the
present case. The terminal group --R.sup.T in the present case may
be a group --R.sup.15 as described in WO 2015/135976 for the
compounds of formula (III).
[0358] GB 1404301.2 and WO 2015/135976 do not explicitly described
polymyxin compounds where the amino acids at positions 6 and/or 7
are substituted with another amino acid.
[0359] Previously, it has been thought that the presence of the Dab
amino acid residue at position 1 of Polymyxin B was not important
for activity, and this amino acid could be deleted. Thus, polymyxin
nonapeptides are known in the art for use in the treatment of
microorganisms.
[0360] The inventors believe that, for optimal activity, an amino
substituent is required to mimic the Dab side chain in the
naturally-occurring polymyxin structure. The inventors have
therefore described in GB 1404301.2 (and also in WO 2015/135976)
compounds where an amino group --NR.sup.16R.sup.17 or
--N(R.sup.16)-- is provided at a carbon atom that is .beta. or
.gamma. to a group --X-- at the N-terminal of a polymyxin
nonapeptide. The group --X-- may be regarded as equivalent to the
carbonyl portion --C(O)-- of an amino acid residue at position 1.
The inventors have found that compounds where an amino group is
provided solely at a carbon atom that is a to the group --X-- have
inferior biological activity.
[0361] Compounds where the amine substituent is provided at a
carbon atom that is .beta. or .gamma. to the group --X-- at the
N-terminal of PMBN have been described in WO 2013/072695. However,
these compounds, if substituted, have a substituent on the carbon
attached to the amine. The inventors have found that it is
important that a further substituent is provided, and furthermore
that this substituent is not on the carbon attached to the amine.
Accordingly the compounds of GB 1404301.2 have an amino group
--NR.sup.16R.sup.17 or --N(R.sup.16)-- that is connected to a
methylene carbon group (--CH.sub.2--).
[0362] In some instances, the stereochemistry is an important
determinant of activity, for example where an additional
substituent is provided at the carbon atom that is a to the group
--X--. In these instances, it is preferred that the stereochemistry
at this position is the same as that of the L-Dab residue in
Polymyxin B.
[0363] Provided that the amino group remains .beta.- or .gamma.- to
the group --X--, the amine group may be part of a
nitrogen-containing heterocycle. WO 2013/072695 describes compounds
having a nitrogen-containing heterocycle at the N terminal of a
nonapeptide. However such compounds are not substituted. The
inventors have found that the addition of a substituent improves
activity. The compounds of GB 1404301.2 (and also WO 2015/135976),
therefore, where the amine --N(R.sup.16)-- is part of a ring
structure, have a ring substituent.
[0364] The compounds of GB 1404301.2 are characterised over the
polymyxin decapeptides for the reason that the compounds of GB
1404301.2 do not possess the amide functionality of a polymyxin
that is formed from the amino group at the a carbon of the L-Dab
group at position 1 and the fatty acyl chain. In the compounds of
the present invention, where an amino group is provided at the a
carbon, it is not part of an amide group. The same comments apply
to the compounds of WO 2015/135976.
[0365] It is known that polymyxin decapeptides derivatives having a
short acyl chain (e.g. butanoyl) connected to the L-Dab residue at
position 1 via an amide bond have poor antibacterial activity. For
instance the pentanoyl and butanoyl derivatives are reported to be
10-20 times less active than Polymyxin B (see de Visser et al. J.
Pept. Res. 2003, 61, 298).
[0366] As noted above, the presence of an amino group solely at the
a carbon is not sufficient to provide good activity. An amino group
at a .gamma. or .gamma. carbon is required. Where an amino group,
such as --NR.sup.16R.sup.17 or --N(R.sup.16)-- is provided at the
.beta. or .gamma. carbon, a further substituted amino group may be
provided at the .alpha. carbon (this amino group is not part of an
amide bond). Such compounds have good activity.
[0367] The compounds described in GB 1404301.2 (and also WO
2015/135976) are compounds corresponding to those of the present
case where -A.sup.1- is absent, -A.sup.2- is an L-threonine or
L-serine residue and -A.sup.3- is an amino acid residue represented
by:
##STR00010##
[0368] where the asterisk is the point of attachment to -A.sup.2-
and --R.sup.3 is C.sub.1-6 alkyl, having one amino or one hydroxyl
substituent.
[0369] Where -A.sup.1-, -A.sup.2- and -A.sup.3- have these
meanings, the group --R.sup.T may an amino-containing group
--R.sup.15.
[0370] In one embodiment, --R.sup.T is an amino-containing
group:
##STR00011##
[0371] where: [0372] --R.sup.A is hydrogen or --L.sup.A-R.sup.AA;
[0373] -Q- is a covalent bond or --CH(R.sup.B)--; [0374] --R.sup.B
is hydrogen or --L.sup.B-R.sup.BB; [0375] or, where -Q- is
--CH(R.sup.B)--, --R.sup.A and --R.sup.B together form a 5- to
10-membered monocyclic or bicyclic carbocycle, or --R.sup.A and
--R.sup.B together form a 5- to 10-monocyclic or bicyclic
heterocycle; [0376] and, where -Q- is a covalent bond, --R.sup.A is
--L.sup.A--R.sup.AA, and where -Q- is --CH(R.sup.B)-- one or both
of --R.sup.A and --R.sup.B is not hydrogen; [0377] --R.sup.16 is
independently hydrogen or C.sub.1-4 alkyl; [0378] --R.sup.17 is
independently hydrogen or C.sub.1-4 alkyl; [0379] or
--NR.sup.16R.sup.17 is a guanidine group; [0380] or --R.sup.17 and
--R.sup.A together form a 5- to 10-membered nitrogen-containing
monocyclic or bicyclic heterocycle; [0381] or, where -Q- is
--CH(R.sup.B)--, --R.sup.17 and --R.sup.B together form a 5- to
10-membered nitrogen-containing monocyclic or bicyclic heterocycle;
[0382] and where --R.sup.17 and --R.sup.A together form a
monocyclic nitrogen-containing heterocycle, each ring carbon atom
in --R.sup.17 and --R.sup.A is optionally mono- or di-substituted
with --R.sup.C, and the monocyclic heterocycle is substituted with
at least one group selected from --R.sup.C, --R.sup.N, --R.sup.NA
and --L.sup.B-R.sup.BB, where present,
[0383] and where --R.sup.17 and --R.sup.B together form a
monocyclic nitrogen-containing heterocycle, each ring carbon atom
in --R.sup.17 and --R.sup.B is optionally mono- or di-substituted
with --R.sup.C, and the monocyclic heterocycle is substituted with
at least one group selected from --R.sup.C, and --R.sup.N, where
present, or the monocyclic heterocycle is optionally substituted
when --R.sup.A is --L.sup.A--R.sup.AA,
[0384] and a monocyclic nitrogen-containing heterocycle optionally
contains one further nitrogen, oxygen or sulfur ring atom, and
where a further nitrogen ring atom is present it is optionally
substituted with --R.sup.N, with the exception of a further
nitrogen ring atom that is connected to the carbon that is a to the
group --X--, which nitrogen ring atom is optionally substituted
with --R.sup.NA;
[0385] where --R.sup.17 and --R.sup.A or --R.sup.17 and --R.sup.B
together form a bicyclic nitrogen-containing heterocycle, each ring
carbon atom in --R.sup.17 and --R.sup.A or --R.sup.17 and --R.sup.B
is optionally mono- or di-substituted with --R.sup.D;
[0386] and the bicyclic nitrogen-containing ring atom heterocycle
optionally contains one, two or three further heteroatoms, where
each heteroatom is independently selected from the group consisting
of nitrogen, oxygen and sulfur, and where further nitrogen ring
atoms are present, each further nitrogen ring atom is optionally
substituted with --R.sup.N, with the exception of a nitrogen ring
atom that is connected to the carbon that is a to the group --X--,
which nitrogen ring atom is optionally substituted with
--R.sup.NA;
[0387] where --R.sup.A and --R.sup.B together form a 5- to
10-membered monocyclic carbocycle or heterocycle, each ring carbon
atom in --R.sup.A and --R.sup.B is optionally mono- or
di-substituted with --R.sup.C, and a nitrogen ring atom, where
present in the monocyclic heterocycle, is optionally substituted
with --R.sup.N, with the exception of a nitrogen ring atom that is
connected to the carbon that is .alpha. to the group --X--, which
nitrogen ring atom is optionally substituted with --R.sup.NA;
[0388] where --R.sup.A and --R.sup.B together form a 5- to
10-membered bicyclic carbocycle or heterocycle, each ring carbon
atom in --R.sup.A and --R.sup.B is optionally mono- or
di-substituted with --R.sup.D, and a nitrogen ring atom, where
present in the bicyclic heterocycle, is optionally substituted with
--R.sup.N, with the exception of a nitrogen ring atom that is
[0389] connected to the carbon that is a to the group --X--, which
nitrogen ring atom is optionally substituted with --R.sup.NA;
[0390] and where R.sup.17 and --R.sup.A or --R.sup.17 and --R.sup.B
together form a 5- to 10-membered nitrogen-containing monocyclic or
bicyclic heterocycle, or where --R.sup.A and --R.sup.B together
form a 5- to 10-membered monocyclic or bicyclic carbocycle, or
together form a 5- to 10-membered monocyclic or bicyclic
heterocycle, a carbon ring atom in --R.sup.17 and --R.sup.A,
--R.sup.17 and --R.sup.B, or --R.sup.A and --R.sup.B is optionally
alternatively substituted with oxo (.dbd.O); [0391] each --R.sup.C
is independently -L.sup.C--R.sup.CC; [0392] each --R.sup.C is
independently selected from --R.sup.C, halo, --NO.sub.2, --OH, and
--NH.sub.2, [0393] each --R.sup.N is independently
-L.sup.N--R.sup.NN; [0394] each --R.sup.NA is independently
--R.sup.L--R.sup.NN or --R.sup.NN. [0395] --R.sup.AA; --R.sup.BB;
and each --R.sup.CC and --R.sup.NN where present, is independently
selected from C.sub.1-12 alkyl, C.sub.3-10 cycloalkyl, C.sub.4-10
heterocyclyl, and C.sub.5-12 aryl; [0396] each --L.sup.A-- is
independently a covalent bond or a linking group selected from
--R.sup.L--*, --O--L.sup.AA-*, --OC(O)--L.sup.AA-*,
--N(R.sup.11)--L.sup.AA-*, and --C(O)--L.sup.AA-*, where the
asterisk indicates the point of attachment of the group -L.sup.A-
to --R.sup.AA; [0397] each -L.sup.B- and -L.sup.C- is independently
a covalent bond or a linking group selected from --R.sup.L-*,
--OC(O)--L.sup.AA-*, --N(R.sup.11)--L.sup.AA-*,
--N(R.sup.11)C(O)--L.sup.AA-*, --C(O)--L.sup.AA-*,
--C(O)O--L.sup.AA-*, and --C(O)N(.sup.R11)-L.sup.AA-*, and
optionally further selected from --N(R.sup.11)S(O)-L.sup.AA-*,
--N(R.sup.11)S(O).sub.2-L.sup.AA-*, --S(O)N(R.sup.11)-L.sup.AA-*,
and --S(O).sub.2N(R.sup.11)-L.sup.AA-* where the asterisk indicates
the point of attachment of the group -L.sup.B- to --R.sup.BB or the
group -L.sup.C- to --R.sup.CC;
[0398] each -L.sup.N- is independently a covalent bond or a group
selected from --S(O)-L.sup.AA-*, --S(O).sub.2-L.sup.AA-*,
--C(O)-L.sup.AA-* and --C(O)N(R.sup.11)-L.sup.AA-*, where the
asterisk indicates the point of attachment of the group -L.sup.N-
to --R.sup.NN;
[0399] and each -L.sup.AA- is independently a covalent bond or
--R.sup.L--;
[0400] and each --R.sup.L-- is independently selected from
C.sub.1-12 alkylene, C.sub.2-12 heteroalkylene, C.sub.3-10
cycloalkylene and C.sub.5-10 heterocyclylene, and where -L.sup.AA-
is connected to a group C.sub.1-12 alkyl, --R.sup.L-- is not
C.sub.1-12 alkylene;
[0401] and each C.sub.1-12 alkyl, C.sub.3-10 cycloalkyl, C.sub.4-10
heterocyclyl, C.sub.5-12 aryl, C.sub.1-12 alkylene, C.sub.2-12
heteroalkylene, C.sub.3-10 cycloalkylene and C.sub.5-10
heterocyclylene group is optionally substituted, where --R.sup.S is
an optional substituent to carbon and --R.sup.12 is an optional
substituent to nitrogen;
[0402] each --R.sup.S is independently selected from --OH,
--OR.sup.12, --OC(O)R.sup.12, halo, --R.sup.12, --NHR.sup.12,
--NR.sup.12R.sup.13, --NHC(O)R.sup.12, --N(R.sup.12)C(O)R.sup.12,
--SH, --SR.sup.12, --C(O)R.sup.12, --C(O)OH, --C(O)OR.sup.12,
--C(O)NH.sub.2, --C(O)NHR.sup.12 and C(O)NR.sup.12R.sup.13; except
that --R.sup.12 is not a substituent to a C.sub.1-12 alkyl group;
or where a carbon atom is di-substituted with --R.sup.S, these
groups may together with the carbon to which they are attached form
a C.sub.3-6 carbocycle or a C.sub.5-6 heterocycle, where the
carbocycle and the heterocycle are optionally substituted with one
or more groups --R.sup.12; [0403] each --R.sup.12 is independently
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, phenyl or benzyl; [0404] each
--R.sup.13 is independently C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
phenyl or benzyl; [0405] or --R.sup.12 and --R.sup.13, where
attached to N, may together form a 5- or 6-membered heterocyclic
ring, which is optionally substituted with C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, phenyl or benzyl;
[0406] each --R.sup.11 is independently hydrogen or C.sub.1-4
alkyl.
[0407] Polymyxin Compounds of Formula (II)
[0408] The compounds of formula (II) are variants of Polymyxin B.
The core of the compound of formula (II) is a variant of a
polymyxin compound, such as a variant of the polymyxin B
decapeptide, nonapeptide (PMBN, Polymyxin 2-10), octapeptide or
heptapetide, where the amino acid at position 6 is substituted with
another amino acid as described herein, and optionally the amino
acid residues at positions 1, 2, 3, 7 and 10 are substituted with
another amino acid residue. Optionally one, two or three of the
amino acid residues at positions 1, 2, 3 may be deleted.
[0409] The N terminal group of the compounds of formula (II), the
group -T.sup.A, is not particularly limited, but certain
preferences are discussed below.
[0410] The compounds of formula (II) may have the same N terminal
groups as the compounds of formula (I). Where this is the case, the
compounds of formula (II) are a selection from the compounds of
formula (I). Thus, the group -T.sup.A may be a group R.sup.T--X--
according to the compounds of formula (I).
[0411] The compounds of formula (I) and (II) allow for substitution
of the amino acid reside at position 6. The substitutions described
for the compounds of formula (II) are a selection of the possible
substitutions described for the compounds of formula (I). The amino
acid residues at 6-postion in the compounds of formula (II) are
believed to be newly disclosed herein. Thus, the amino acid residue
at position 6 is not believed to be described in Velkov et al., WO
2010/130007 or WO 2012/051663.
[0412] Velkov et al. describe substitutions at the 6-position of
Polymyxin B and colistin. The authors disclose the replacement of
D-phenylalanine or D-leucine at position 6 with three different
amino acid residues. Each amino acid differs from phenylalanine and
leucine in the nature of the amino acid side group. Thus, the
phenyl group of phenylalanine or the butyl group of leucine is
replaced with octyl (D-OctGly), diphenylmethyl (D-BipAla) or
benzyl-protected 4-hydroxyphenyl (D-Tyr(Bzl). No other
modifications to the 6-position are described or suggested.
[0413] Velkov et al. also describe the modification of the
polymyxin N terminal group along with the 6-postion substitution.
Thus, the methyloctanoyl or methylheptanoyl terminal group of
Polymyxin B is replaced with octanoyl, biphenylacyl, or
phenacyl.
[0414] The supplementary information accompanying Velkov et al.
shows that compounds carrying a D-OctGly, D-BipAla or a D-Tyr(Bzl)
substitution at the 6-position have activity against P. aeruginosa,
A. baumannii and K. pneumoniae strains, with MIC values in the
range 2-32 mg/L. The variants are also said to have activity
against polymyxin-resistant strains of P. aeruginosa, A. baumannii
and K. pneumoniae amongst others.
[0415] WO 2010/130007 broadly describes substitutions at the 6- and
7-positions of polymyxin. The worked examples however only
demonstrate the preparation of compounds that are substituted at
the 7-position. All the worked examples retain D-phenylalanine at
position 6. The polymyxin N terminal group is also modified. The
worked examples have an octanoyl, nonanoyl or biphenylacyl group at
the N terminal.
[0416] WO 2012/051663 broadly describes substitutions at the 6- and
7-positions of polymyxin. The worked examples include compounds
where the 6-position is substituted. However, the examples are
limited. In one example, the amino acid residue at position 6 is
D-OctGly and in another example the amino acid residue at position
6 is D-Cys(S-Hex) (i.e. a cysteine amino acid where the thiol group
is a hexylthio group). The polymyxin N terminal group is also
modified. The worked examples have an octanoyl, decanoyl,
biphenylacyl or biphenylmethylacyl group at the N terminal.
[0417] The inventors have found that certain alternative
substitutions at the 6-postion provide compounds having
antimicrobial activity, for example against Gram-negative bacteria,
such as against E. coli, P. aeruginosa, K. pneumonia, and A.
Baumannii.
[0418] Such substitutions may also enhance antimicrobial activity
compared with the parent unmodified compounds. As shown in the
present case, compound 2 is a Polymyxin B variant, where the
phenylalanine amino acid residue at position 6 is replaced with a
phenylalanine analogue bearing a bromo substituent at the
4-position of the phenyl group. Compound 2 has superior activity to
Polymyxin B against many E. coli, P. aeruginosa, K. pneumonia, and
A. Baumannii strains.
[0419] The compounds of formula (II) encompass compounds having
amio acid residues at position 6 that are stucturally non-obvious
in the light of earlier work by Velkov et al.
[0420] The present invention provides a compound of formula (II)
and the use of this compound in a method of treatment. The compound
of formula (II) is represented thus:
##STR00012##
[0421] wherein:
[0422] -T.sup.A is hydrogen, C.sub.1-4 alkyl or R.sup.N--X--;
[0423] -A.sup.1- is absent or is an amino acid residue;
[0424] -A.sup.2- is absent or is an amino acid residue;
[0425] -A.sup.3- is absent or is an amino acid residue;
[0426] --X-- is --C(O)--, --NHC(O)--, --OC(O)--, --CH.sub.2-- or
--SO.sub.2--;
[0427] --R.sup.N is a terminal group, such as a group --R.sup.T as
described herein;
[0428] --R.sup.6A is C.sub.1-12 alkyl, C.sub.0-12 alkyl (C.sub.3-10
cycloalkyl), C.sub.0-12 alkyl (C.sub.3-10 heterocyclyl) or
C.sub.0-12 alkyl (C.sub.5-10 aryl), where the C.sub.1-12 alkyl,
C.sub.3-10 cycloalkyl group C.sub.3-10 heterocyclyl group, and the
C.sub.5-10 aryl group are optionally substituted, and the optional
substituents are as described herein, and with the proviso that
--R.sup.6A is not benzyl, iso-butyl, iso-propyl, and optionally
--R.sup.6A is not methyl, phenyl, 4-hydroxyphenyl, (1H-indol-3-yl)
methyl, 4-phenylphen-1-yl methyl, --(CH.sub.2).sub.7CH.sub.3,
4-(OBn)-phen-1-yl methyl or --CH.sub.2S(CH.sub.2).sub.5CH.sub.3,
and optionally --R.sup.6A is not n-propyl, n-butyl, or
tert-butyl;
[0429] --R.sup.7A together with the carbonyl group and nitrogen
alpha to the carbon to which it is attached is an amino acid
residue;
[0430] R.sup.10 together with the carbonyl group and nitrogen alpha
to the carbon to which it is attached, is a threonine or leucine
residue;
[0431] and salts, solvates, protected forms and/or prodrug forms
thereof.
[0432] It is noted that compounds of formula (II) where --T.sup.A
is hydrogen (--H) may be used as intermediates for the preparation
of compounds of formula (I) and other compounds of formula (II),
where --T.sup.A is C.sub.1-4 alkyl or R.sup.N--X--.
[0433] In one embodiment, the compound of formula (II) is
represented thus:
##STR00013##
[0434] --R.sup.6A
[0435] In one embodiment, --R.sup.6A is C.sub.1-12 alkyl,
C.sub.0-12 alkyl(C.sub.3-10 cycloalkyl), C.sub.0-12
alkyl(C.sub.3-10 heterocyclyl) or C.sub.0-12 alkyl(C.sub.5-10
aryl), where the C.sub.1-12 alkyl, C.sub.3-10 cycloalkyl group
C.sub.3-10 heterocyclyl group, and the C.sub.5-10 aryl group are
optionally substituted.
[0436] In one embodiment, --R.sup.6A is C.sub.0-12 alkyl(C.sub.3-10
cycloalkyl), C.sub.0-12 alkyl(C.sub.3-10 heterocyclyl) or
C.sub.0-12 alkyl(C.sub.5-10 aryl), where the C.sub.3-10 cycloalkyl
group, C.sub.3-10 heterocyclyl group, and the C.sub.5-10 aryl group
are optionally substituted.
[0437] In one embodiment, --R.sup.6A is C.sub.0-12 alkyl(C.sub.3-10
cycloalkyl) or C.sub.0-12 alkyl(C.sub.5-10 aryl), where the
C.sub.3-10 cycloalkyl group and the C.sub.5-10 aryl group are
optionally substituted.
[0438] In one embodiment, the group --R.sup.6A is not benzyl,
iso-butyl or iso-propyl (the residue at position 6 may not be
phenylalanine, leucine or valine, and particularly the D-forms
thereof).
[0439] additionally or alternatively, in one embodiment the group
--R.sup.6A is not methyl, 4-hydroxyphenyl, (1 H-indol-3-yl) methyl
or phenyl (the residue at position 6 may not be alanine, tyrosine,
tryptophan and phenylglycine).
[0440] In one embodiment, the group --R.sup.6A is not
4-phenylphen-1-yl methyl, --(CH.sub.2).sub.7CH.sub.3,
4-(OBn)-phen-1-yl or --CH.sub.2S(CH.sub.2).sub.5CH.sub.3.
[0441] Additionally or alternatively, the residue at position 6 may
not be norvaline, norleucine and t-butylglycine, particularly the
D-forms thereof. Thus, the group --R.sup.6A may not be n-propyl,
n-butyl and tert-butyl.
[0442] Alternatively, the residue at position 6 may not be
phenylalanine, leucine, norvaline, norleucine and t-butylglycine,
particularly the D-forms thereof. Thus, the group --R.sup.6A may
not be benzyl, iso-butyl, n-propyl, n-butyl and tert-butyl.
[0443] The C.sub.1-12 alkyl group, C.sub.3-10 cycloalkyl group,
C.sub.3-10 heterocyclyl group, and the C.sub.5-10 aryl group may be
substituted, such as optionally substituted with one or more groups
--R.sup.Z, where each group --R.sup.Z is selected from halo,
optionally substituted C.sub.1-12 alkyl, optionally substituted
C.sub.2-12 alkenyl, optionally substituted C.sub.2-12 alkynyl,
optionally substituted C.sub.3-10 cycloalkyl, optionally
substituted C.sub.3-10 heterocyclyl, optionally substituted
C.sub.5-12 aryl, --CN, --NO.sub.2, --OR.sup.Q, --SR.sup.Q,
--N(R.sup.W)C(O)R.sup.Q, --N(R.sup.Q).sub.2, and
--C(O)N(R.sup.Q).sub.2, [0444] where --R.sup.W is H or C.sub.1-4
alkyl; and [0445] --R.sup.Q is H or --R.sup.Q1, and --R.sup.Q1 is
selected from optionally substituted C.sub.1-12 alkyl, C.sub.2-12
alkenyl, C.sub.2-12 alkynyl, and C.sub.5-12 aryl,
[0446] and in a group --N(R.sup.Q).sub.2 the groups --R.sup.Q may
together with the nitrogen atom to which they are attached form a
C.sub.5-6 heterocycle, where the heterocycle is optionally
substituted, [0447] with the proviso that C.sub.1-12 alkyl is not
substituted with alkyl, alkenyl or alkynyl.
[0448] The group --R.sup.6A together with the carbonyl group and
nitrogen alpha to the carbon to which it is attached is not a
leucine, iso-leucine, phenylalanine, threonine, valine or
nor-valine residue. Additionally or alternatively, --R.sup.6A
together with the carbonyl group and nitrogen alpha to the carbon
to which it is attached is not a tyrosine residue.
[0449] As noted above, the C.sub.1-12 alkyl group, C.sub.3-10
cycloalkyl group, C.sub.3-10 heterocyclyl group, and the C.sub.5-10
aryl group may be substituted with one or more groups --R.sup.Z.
Examples of --R.sup.Z include optionally substituted alkyl,
alkenyl, alkynyl, cycloalkyl, aryl and heterocycle groups.
[0450] Where a group, such as alkyl, alkenyl, alkynyl, cycloalkyl,
aryl and heterocycle, is optionally substituted, the group may have
one or more substituent groups selected from halo, haloalkyl,
alkyl, alkenyl, alkynyl, and aryl, except that alkyl alkenyl, and
alkynyl groups are not substituents to the alkyl alkenyl, and
alkynyl groups. Suitable groups are described in relation to the
definition of --R.sup.P for --R.sup.6.
[0451] In one embodiment, --R.sup.6A is C.sub.0-12 alkyl(C.sub.5-10
aryl), where the C.sub.5-10 aryl group is optionally substituted,
and the C.sub.5-10 aryl group is substituted with one or more
groups --R.sup.Z, where each group --R.sup.Z is selected from halo,
optionally substituted C.sub.1-12 alkyl, --CN, and --NO.sub.2.
[0452] In one embodiment, --R.sup.6A is C.sub.0-12 alkyl(C.sub.5-10
aryl), where the C.sub.5-10 aryl group is optionally substituted,
and the C.sub.5-10 aryl group is substituted with one or more
groups --R.sup.Z, where each group --R.sup.Z is selected from halo,
optionally substituted C.sub.1-12 alkyl, optionally substituted
C.sub.2-12 alkenyl, --CN, and --NO.sub.2.
[0453] In one embodiment, --R.sup.6A is C.sub.0-12 alkyl(C.sub.3-10
cycloalkyl), where the C.sub.3-10 cycloalkyl group is optionally
substituted, and the C.sub.3-10 cycloalkyl group is substituted
with one or more groups --R.sup.Z, where each group --R.sup.Z is
selected from halo, optionally substituted C.sub.1-12 alkyl,
optionally substituted C.sub.2-12 alkenyl, optionally substituted
C.sub.2-12 alkynyl, optionally substituted C.sub.3-10 cycloalkyl,
optionally substituted C.sub.3-10 heterocyclyl, optionally
substituted C.sub.5-12 aryl, --OR.sup.Q, --SR.sup.Q,
--N(R.sup.W)C(O)R.sup.Q, --N(R.sup.Q).sub.2, and
--C(O)N(R.sup.Q).sub.2.
[0454] In one embodiment, --R.sup.6A is C.sub.0-12 alkyl(C.sub.6
cycloalkyl), such as C.sub.1 alkyl(C.sub.6 cycloalkyl). The worked
examples in the present case include numerous compounds where the
group --R.sup.6A is C.sub.1 alkyl(C6 cycloalkyl)
(--CH.sub.2(C.sub.6H.sub.11)).
[0455] In one embodiment, --R.sup.6A is optionally substituted
C.sub.1-12 alkyl, where the C.sub.1-12 alkyl is optionally
substituted with one or more groups selected from halo, such as
fluoro, optionally substituted C.sub.3-10 cycloalkyl, optionally
substituted C.sub.3-10 heterocyclyl, optionally substituted
C.sub.5-12 aryl, --CN, --NO.sub.2, --OR.sup.Q, --SR.sup.Q,
--N(R.sup.W)C(O)R.sup.Q, --N(R.sup.Q).sub.2, and
--C(O)N(R.sup.Q).sub.2.
[0456] In one embodiment, --R.sup.6A is optionally substituted
C.sub.1-12 alkyl.
[0457] The alkyl group is typically a C.sub.1-12 alkyl group, such
as C.sub.2-12 alkyl, such as C.sub.s-12 alkyl, such as C.sub.4-12
alkyl, such as C.sub.5-12 alkyl, such as C.sub.6-12 alkyl, such as
C.sub.8-12 alkyl, for example C.sub.2-10 alkyl, C.sub.4-10 alkyl,
C.sub.5-10 alkyl and C.sub.6-10 alkyl.
[0458] The alkyl group may be a C.sub.9-12 alkyl group, such as
C.sub.9, C.sub.11 and C.sub.12 alkyl.
[0459] The alkyl group may be a C.sub.1-5 alkyl group.
[0460] The alkyl group may be a C.sub.5-12 alkyl group.
[0461] In one embodiment, --R.sup.6A is optionally substituted
C.sub.2-12 alkyl.
[0462] The alkyl group may be linear or branched.
[0463] Where the alkyl group is substituted, it may be
monosubstituted. A substituent may be provided at a terminal of the
alkyl group.
[0464] A C.sub.0-12 alkyl group may be a C.sub.1-12 alkyl group,
such a C.sub.2-12 alkyl group, a C.sub.1-3 alkyl group, and a
C.sub.5-12 alkyl group.
[0465] In one embodiment, a C.sub.0-12 alkyl group is C.sub.1
alkyl.
[0466] In one embodiment, a C.sub.0-12 alkyl group is C.sub.0
alkyl.
[0467] In one embodiment, a C.sub.0-12 alkyl group is not linear
C.sub.4 alkyl.
[0468] In one embodiment, a C.sub.0-12 alkyl group is not C.sub.0
alkyl and/or C.sub.1 alkyl.
[0469] In one embodiment, --R.sup.6A is not
--CH.sub.2S(CH.sub.2).sub.5CH.sub.3,
--CH.sub.2O(CH.sub.2).sub.5CH.sub.3,
--CH.sub.2S(CH.sub.2).sub.5CF.sub.3, --CH2OCH2Ph, or
--CH.sub.2SCH.sub.2Ph.
[0470] In one embodiment, --R.sup.6A is C.sub.0-12 alkyl(C.sub.5-10
aryl), such as C.sub.1-12 alkyl(C.sub.5-10 aryl), where the
C.sub.5-10 aryl group is optionally substituted.
[0471] In one embodiment, --R.sup.6A is C.sub.0-1 alkyl(C.sub.5-10
aryl).
[0472] In one embodiment, --R.sup.6A is C.sub.2-12 alkyl(C.sub.5-10
aryl).
[0473] In one embodiment, --R.sup.6A is C.sub.0-12 alkyl(C.sub.5-10
heteroaryl).
[0474] In one embodiment, --R.sup.6A is C.sub.0-12 alkyl(C.sub.5-10
aryl), where the aryl is optionally substituted with halo,
optionally substituted C.sub.2-12 alkenyl, optionally substituted
C.sub.2-12 alkynyl, substituted C.sub.3-10 cycloalkyl, optionally
substituted C.sub.3-10 heterocyclyl, substituted C.sub.5-12 aryl,
--CN, --NO.sub.2, --SR.sup.Q, --N(R.sup.W)C(O)R.sup.Q,
--N(R.sup.Q).sub.2, and --C(O)N(R.sup.Q).sub.2.
[0475] In one embodiment, --R.sup.6A is C.sub.0-12 alkyl(C.sub.5-10
aryl), where the aryl is optionally substituted with halo,
optionally substituted C.sub.2-12 alkenyl, optionally substituted
C.sub.2-12 alkynyl, optionally substituted C.sub.3-10 heterocyclyl,
--CN, --NO.sub.2, --SR.sup.Q, --N(R.sup.W)C(O)R.sup.Q,
--N(R.sup.Q).sub.2, and --C(O)N(R.sup.Q).sub.2.
[0476] The aryl group may be a carboaryl or heteroaryl group.
[0477] The carboaryl group may be phenyl. The alkyl group may be
linear or branched.
[0478] In one embodiment, --R.sup.6A is substituted benzyl
(--CH.sub.2Ph).
[0479] In one embodiment, --R.sup.6A is monosubstituted benzyl.
[0480] In one embodiment, --R.sup.6A is monosubstituted benzyl,
where the phenyl group is substituted at the 2-, 3- or 4-position,
such as the 2- or 4-position.
[0481] In one embodiment, --R.sup.6A is monosubstituted benzyl,
where the phenyl group is substituted at the 2-position with halo,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted cycloalkyl, or optionally substituted
aryl.
[0482] In one embodiment, --R.sup.6A is monosubstituted benzyl,
where the phenyl group is substituted at the 2-position with halo,
optionally substituted alkyl, optionally substituted cycloalkyl, or
optionally substituted aryl.
[0483] In one embodiment, --R.sup.6A is monosubstituted benzyl,
where the phenyl group is substituted at the 2-position with halo,
optionally substituted alkyl, or optionally substituted aryl.
[0484] In one embodiment, --R.sup.6A is monosubstituted benzyl,
where the phenyl group is substituted at the 4-position with halo,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted aryl or optionally substituted
heteroaryl.
[0485] In one embodiment, --R.sup.6A is monosubstituted benzyl,
where the phenyl group is substituted at the 4-position with halo,
optionally substituted alkyl, optionally substituted aryl or
optionally substituted heteroaryl.
[0486] In one embodiment, --R.sup.6A is monosubstituted benzyl,
where the phenyl group is substituted at the 4-position with halo,
optionally substituted alkyl, substituted aryl or optionally
substituted heteroaryl.
[0487] In one embodiment, --R.sup.6A is monosubstituted benzyl,
where the phenyl group is substituted at the 3-position with halo,
optionally substituted alkyl, optionally substituted alkenyl,
substituted aryl or optionally substituted heteroaryl.
[0488] In one embodiment, --R.sup.6A is monosubstituted benzyl,
where the phenyl group is substituted at the 3-position with halo,
optionally substituted alkyl, substituted aryl or optionally
substituted heteroaryl.
[0489] In one embodiment, --R.sup.6A is monosubstituted benzyl,
where the phenyl group is substituted at the 2-position with aryl,
such as phenyl.
[0490] In one embodiment, --R.sup.6A is monosubstituted benzyl,
where the phenyl group is substituted at the 3-position with aryl,
such as C.sub.5-10 aryl, such as C.sub.5-6 aryl, such as phenyl or
pyridine. The aryl group is optionally substituted, such as
substituted.
[0491] In one embodiment, --R.sup.6A is monosubstituted benzyl,
where the phenyl group is substituted at the 4-position with aryl,
such as C.sub.5-10 aryl, such as C.sub.5-6 aryl, such as phenyl or
pyridine. The aryl group is optionally substituted, such as
substituted.
[0492] In one embodiment, --R.sup.6A is monosubstituted benzyl,
where the phenyl group is substituted at the 3-position with
heteroaryl, such as C.sub.5-10 heteroaryl, such as C.sub.5-6
heteroaryl, such as pyridine.
[0493] In one embodiment, --R.sup.6A is monosubstituted benzyl,
where the phenyl group is substituted at the 4-position with
heteroaryl, such as C5-10 heteroaryl, such as C.sub.5-6 heteroaryl,
such as pyridine.
[0494] In one embodiment, --R.sup.6A is monosubstituted benzyl,
where the phenyl group is substituted at the 3-position with halo,
such as bromo.
[0495] In one embodiment, --R.sup.6A is monosubstituted benzyl,
where the phenyl group is substituted at the 4-position with halo,
such as bromo.
[0496] In one embodiment, --R.sup.6A is monosubstituted benzyl,
where the phenyl group is substituted at the 3-position with alkyl,
such as C.sub.1-12 alkyl, such as C.sub.2-12 alkyl, such as
C.sub.6-12 alkyl, such as C.sub.8 alkyl. The alkyl group may be
linear or branched.
[0497] In one embodiment, --R.sup.6A is monosubstituted benzyl,
where the phenyl group is substituted at the 4-position with alkyl,
such as C.sub.1-12 alkyl, such as C.sub.2-12 alkyl, such as
C.sub.6-12 alkyl, such as C.sub.8 alkyl. The alkyl group may be
linear or branched.
[0498] In one embodiment, --R.sup.6A is C.sub.0-12 alkyl(C.sub.3-10
cycloalkyl), such as C.sub.1-12 alkyl(C.sub.3-10 cycloalkyl), where
the C.sub.3-10 cycloalkyl group is optionally substituted.
[0499] In one embodiment, --R.sup.6A is C.sub.1 alkyl(C.sub.3-10
cycloalkyl), such as C.sub.1 alkyl(cyclohexyl), where the
C.sub.3-10 cycloalkyl group is optionally substituted.
[0500] In one embodiment, --R.sup.6A is C.sub.1-12
alkyl(cyclohexyl). Compounds of this type may be prepared from
compounds where --R.sup.6A is C.sub.1-16 alkyl(phenyl) by
appropriate reduction of the phenyl group, such as described
herein.
[0501] In one embodiment, --R.sup.6A is C.sub.0-12 alkyl(C.sub.3-10
cycloalkyl), such as C.sub.1 alkyl(cyclohexyl), where the
C.sub.3-10 cycloalkyl group is optionally substituted with one or
more groups selected from halo, substituted C.sub.1-12 alkyl,
optionally substituted C.sub.2-12 alkenyl, optionally substituted
C.sub.2-12 alkynyl, optionally substituted C.sub.3-10 cycloalkyl,
optionally substituted C.sub.3-10 heterocyclyl, optionally
substituted C.sub.5-12 aryl, --CN, --NO.sub.2, --OR.sup.Q,
--SR.sup.Q, --N(R.sup.W)C(O)R.sup.Q, --N(R.sup.Q).sub.2, and
--C(O)N(R.sup.Q).sub.2.
[0502] In one embodiment, --R.sup.6A is C.sub.0-12 alkyl(C.sub.3-10
cycloalkyl), such as C.sub.1 alkyl(cyclohexyl), where the
C.sub.3-10 cycloalkyl group is optionally substituted with one or
more groups selected from halo, optionally substituted C.sub.2-12
alkenyl, optionally substituted C.sub.2-12 alkynyl, optionally
substituted C.sub.3-10 cycloalkyl, optionally substituted
C.sub.3-10 heterocyclyl, optionally substituted C.sub.5-12 aryl,
--CN, --NO.sub.2, --OR.sup.Q, --SR.sup.Q, --N(R.sup.W)C(O)R.sup.Q,
--N(R.sup.Q).sub.2, and --C(O)N(R.sup.Q).sub.2.
[0503] The C.sub.3-10 cycloalkyl may be a C.sub.5-7 cycloalkyl
group, such as C.sub.5-6 cycloalkyl group.
[0504] In one embodiment, C.sub.3-10 cycloalkyl is cyclopentyl or
cyclohexyl, such as cyclohexyl.
[0505] A cycloalkyl group may be optionally substituted, such as
optionally monosubstituted.
[0506] Where, the cycloalkyl group is cyclohexyl, the cyclohexyl is
optionally substituted at the 2-, 3- or 4-position, such as the 2-
or 4-position, such as the 4-position.
[0507] In one embodiment, --R.sup.6 and/or --R.sup.7 is not
--(CH.sub.2).sub.4-cyclcohexyl.
[0508] In one embodiment, --R.sup.6 and/or --R.sup.7 is not
--(C.sub.6H.sub.10)--Pr, such as where the -Pr group is a linear
propyl group.
[0509] In one embodiment, --R.sup.6A is C.sub.0-12 alkyl(C.sub.3-10
heterocyclyl) such as C.sub.1-12 alkyl(C.sub.3-10 heterocyclyl),
where the C.sub.3-10 heterocyclyl group is optionally substituted.
Where C.sub.0-12 alkyl is C.sub.0, the heteroatom of the
heterocyclyl group is not provided at the .beta. position (i.e. the
heteroatom is not connected to the a carbon).
[0510] The heterocyclyl group contains a heteroatom selected from
N, O and S, and optionally contains further heteroatoms. A
reference to N is a reference to a group --NH-- within a
heterocycle, and a reference to S is --S--, --S(O)-- or
--S(O).sub.2--.
[0511] The heterocyclyl may be substituted at a carbon ring atom or
a nitrogen ring atom, if such is present. Where a nitrogen ring
atom is substituted the substituent may be a group --R.sup.Z
selected from optionally substituted C.sub.1-12 alkyl, optionally
substituted C.sub.2-12 alkenyl, optionally substituted C.sub.2-12
alkynyl, optionally substituted C.sub.3-10 cycloalkyl, optionally
substituted C.sub.3-10 heterocyclyl, optionally substituted
C.sub.5-12 aryl, and --C(O)N(R.sup.Q).sub.2. Where a carbon ring
atom is substituted the substituent may be a group --R.sup.Z such
as described above.
[0512] The heterocyclyl may be C.sub.5-10, such as C.sub.5-6, such
as C.sub.5 or C.sub.6 heterocyclyl.
[0513] The heterocyclyl may be selected from the group consisting
of piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl.
[0514] Where an alkyl group is optionally substituted with halo, it
is preferred that the alkyl group is optionally substituted with
fluoro.
[0515] In one embodiment, --R.sup.6A is not 4-hydroxyphenylmethyl
(i.e. --R.sup.6 together with the carbonyl group and nitrogen alpha
to the carbon to which it is attached is not a tyrosine
residue).
[0516] The comments above refer to compounds where the a amino acid
residue at position 6 has a a carbon atom that is substituted with
--R.sup.6A and --H. The --H may also be a site for substitution,
providing di-substituted a amino acid residues at position 6.
[0517] In an alternative embodiment, a carbon atom at within the a
amino acid residue at position 6 is di-substituted, where each
substituent is a group --R.sup.6A as described herein.
[0518] In an alternative embodiment, the a carbon atom at within
the a amino acid residue at position 6 is di-substituted, where
each substituent is a group --R.sup.6A, where the groups --R.sup.6A
may together with the .alpha. carbon atom to which they are
attached form a C.sub.4-6 carbocycle or a C.sub.5-6 heterocycle,
wherein the carbocycle and the heterocycle are optionally
substituted with one or more groups --R.sup.Z, as described above.
The carbocycle is a cycloalkyl group as described herein. The
heterocycle is a heterocyclyl group as described herein.
[0519] Where a heterocycle is present the heteroatom of the
heterocyclyl group is not provided at the .beta. position (i.e. the
heteroatom is not connected to the a carbon).
[0520] The heterocycle contains a heteroatom selected from N, O and
S, and optionally contains further heteroatoms. A reference to N is
a reference to a group --NH-- within a heterocycle, and a reference
to S is --S--, --S(O)-- or --S(O).sub.2--.
[0521] The heterocyclyl may be substituted at a carbon ring atom or
a nitrogen ring atom, if such is present. Where a nitrogen ring
atom is substituted the substituent may be a group --R.sup.Z
selected from optionally substituted C.sub.1-12 alkyl, optionally
substituted C.sub.2-12 alkenyl, optionally substituted C.sub.2-12
alkynyl, optionally substituted C.sub.3-10 cycloalkyl, optionally
substituted C.sub.3-10 heterocyclyl, optionally substituted
C.sub.5-12 aryl, and --C(O)N(R.sup.Q).sub.2. Where a carbon ring
atom is substituted the substituent may be a group --R.sup.Z such
as described above.
[0522] The heterocycle may be selected from the groups piperidine,
piperazine, morpholine and thiomorpholine.
[0523] In one embodiment, --R.sup.6A together with the carbonyl
group and nitrogen alpha to the carbon to which it is attached is
an amino having a piperidine side chain that is a gem
di-substituent to the .alpha.-carbon. Thus the .alpha.-carbon is a
ring atom in the piperidine ring. This is a cyclic analogue of
Dab.
[0524] In one embodiment, --R.sup.Z is selected from halo,
optionally substituted C.sub.1-12 alkyl, optionally substituted
C.sub.2-12 alkenyl, optionally substituted C.sub.2-12 alkynyl,
optionally substituted C.sub.5-12 aryl, --OR.sup.Q, --SR.sup.Q,
--N(R.sup.W)C(O)R.sup.Q, --N(R.sup.Q).sub.2, and
--C(O)N(R.sup.Q).sub.2.
[0525] In one embodiment, --R.sup.Z is selected from halo,
optionally substituted C.sub.2-12 alkenyl, optionally substituted
C.sub.2-12 alkynyl, optionally substituted C.sub.3-10 cycloalkyl,
optionally substituted C.sub.5-12 aryl, --OR.sup.Q, --SR.sup.Q,
--N(R.sup.W)C(O)R.sup.Q, --N(R.sup.Q).sub.2, and
--C(O)N(R.sup.Q).sub.2.
[0526] In one embodiment, --R.sup.Z is selected from halo,
optionally substituted C.sub.2-12 alkenyl, optionally substituted
C.sub.2-12 alkynyl, optionally substituted C.sub.5-12 aryl,
--OR.sup.Q, --SR.sup.Q, --N(R.sup.W)C(O)R.sup.Q,
--N(R.sup.Q).sub.2, and --C(O)N(R.sup.Q).sub.2.
[0527] In one embodiment, --R.sup.Z is selected from halo,
optionally substituted C.sub.1-12 alkyl, optionally substituted
C.sub.2-12 alkenyl, optionally substituted C.sub.2-12 alkynyl,
optionally substituted C.sub.3-10 cycloalkyl, --OR.sup.Q,
--SR.sup.Q, --N(R.sup.W)C(O)R.sup.Q, --N(R.sup.Q).sub.2, and
--C(O)N(R.sup.Q).sub.2.
[0528] In one embodiment, --R.sup.Z is selected from halo,
optionally substituted C.sub.2-12 alkenyl, optionally substituted
C.sub.2-12 alkynyl, --OR.sup.Q, --SR.sup.Q,
--N(R.sup.W)C(O)R.sup.Q, --N(R.sup.Q).sub.2, and
--C(O)N(R.sup.Q).sub.2.
[0529] In one embodiment, the amino acid residue at position 6 is
an L- or D-amino acid residue, such as a D-amino acid residue.
[0530] --R.sup.7A
[0531] In one embodiment, --R.sup.7A together with the carbonyl
group and nitrogen alpha to the carbon to which it is attached may
be a leucine, iso-leucine, phenylalanine, threonine, valine or
nor-valine residue
[0532] In one embodiment, the group --R.sup.7A may be a group
--R.sup.7 as described above for the compounds of formula (I).
[0533] In one embodiment, --R.sup.7A together with the carbonyl
group and nitrogen alpha to the carbon to which it is attached is
an amino acid residue selected from the group consisting of
leucine, OctGly, BipAla, and Cys, such as Cys(S-Hex) and
Cys(S-Bzl), and for example the L-forms thereof. Additionally or
alternatively, --R.sup.7A together with the carbonyl group and
nitrogen alpha to the carbon to which it is an amino acid residue
selected from the group consisting of threonine, serine, valine,
2-aminobutyric acid (Abu) and 2-aminoisobutyric acid (Aib), and for
example the L-forms thereof.
[0534] In one embodiment, --R.sup.7A together with the carbonyl
group and nitrogen alpha to the carbon to which it is a leucine
residue, such as L-leucine. In this embodiment, the amino acid
residue at the 7-position is not substituted with reference to the
amino acid residue at the 7-position of Polymyxin B.
[0535] In one embodiment, --R.sup.7A together with the carbonyl
group and nitrogen alpha to the carbon to which it is attached is
an amino acid residue selected from the group consisting of
leucine, alanine, phenylalanine, OctGly, BipAla, Cys, such as
Cys(S-Hex) and Cys(S-Bzl), threonine, serine, valine,
2-aminobutyric acid (Abu) and 2-aminoisobutyric acid (Aib), and for
example the L-forms thereof.
[0536] In one embodiment, the amino acid residue at position 7 is
an L- or D-amino acid residue, such as an L-amino acid residue.
[0537] --T.sup.A
[0538] In one embodiment, --T.sup.A is hydrogen or
--X--R.sup.N.
[0539] In one embodiment, --T.sup.A is hydrogen. Such a compound
has a free amino group (primary amine, --NH.sub.2) at the N
terminal.
[0540] In one embodiment, --T.sup.A is C.sub.1-4 alkyl. Here, the
compound has an alkylated amino group at the N terminal. The
C.sub.1-4 alkyl group may be linear or branched. The C.sub.1-4
alkyl group may be selected from methyl, ethyl, propyl and butyl,
such as methyl and ethyl. The C.sub.1-4 alkyl group may be
methyl.
[0541] In one embodiment, --T.sup.A is --X--R.sup.N. Here, the N
terminal group of the compound is modified. Modifications to the N
terminal are well known in the art. Indeed, the natural
products
[0542] Polymyxin B and Colistin are also modified at the N
terminal.
[0543] --X--
[0544] The group --X-- is as defined from the compounds of formula
(I).
[0545] --R.sup.N
[0546] The group --R.sup.N is a terminal group.
[0547] The terminal group may be a group that retains biological
activity or provides improved biological activity when that group
is compared with the terminal group present in Polymyxin B and
Colistin.
[0548] In one embodiment, the group --R.sup.N is a group --R.sup.T
as defined above for the compounds of formula (I). The group
--R.sup.T typically possesses hydroxyl and/or amino
functionality.
[0549] Alternatively, the group --R.sup.N may be a lipophilic
group.
[0550] In one embodiment, --R.sup.N is benzyl. In one embodiment,
--R.sup.N is M-L.sup.11-L.sup.10-, where: [0551] -L.sup.10- is a
covalent bond, C.sub.1-12 alkylene or C.sub.2-12 heteroalkylene,
[0552] -M is selected from optionally substituted C.sub.1-12 alkyl,
C.sub.2-12 alkenyl, C.sub.3-10 cycloalkyl and C.sub.5-12 aryl,
[0553] and with the proviso that -L.sup.10- is not C.sub.1-12
alkylene when -M is C.sub.1-12 alkyl.
[0554] The optional substituents may be selected from the group
consisting of optionally substituted C.sub.1-10 alkyl, C.sub.2-12
alkenyl, C.sub.5-12 aryl, C.sub.3-10 cycloalkyl, --OH, --OR.sup.19,
--NH.sub.2, --NHR.sup.19, --N(R.sup.19).sub.2, --COOR.sup.19,
--OCOR.sup.19, --CON(R.sup.10).sub.2, and --NR.sup.10C(O)R.sup.10,
where each --R.sup.19 is independently C.sub.1-10 alkyl, C.sub.2-12
alkenyl, C.sub.5-12 aryl, C.sub.3-10 cycloalkyl, and the optional
substituents are --OH and --NH.sub.2.
[0555] In one embodiment, --R.sup.N is selected from optionally
substituted C.sub.1-12 alkyl and -L.sup.12-V, where -L.sup.12- is
absent or C.sub.2-4 alkenyl, and V-- is optionally substituted
C.sub.5-12 aryl, such as C.sub.6-10 carboaryl and C.sub.5-12
heteroaryl, where the optional substituent is W-L.sup.12-, and:
[0556] -L.sup.13- is a covalent bond, C.sub.1-3 alkylene or
C.sub.2-7 heteroalkylene, [0557] --W is C.sub.5-12 aryl, such as
C.sub.6-10 carboaryl and C.sub.5-12 heteroaryl.
[0558] In one embodiment, --R.sup.N is C.sub.1-12 alkyl.
[0559] A C.sub.1-12 alkyl group may be a C.sub.4-12, C.sub.6-12,
C.sub.4-10 or a C.sub.6-10 alkyl group.
[0560] An alkyl group may be linear or branched.
[0561] In one embodiment, the alkyl group is C.sub.6-8 alkyl. As
noted above, an alkyl group may be linear or branched. Where the
C.sub.6-8 alkyl group is branched, the branch point may be located
at the penultimate carbon of the longest linear alkyl chain. The
branch may be a methyl branch.
[0562] In one embodiment, --R.sup.N is 5-methylheptyl, for example
where --X-- is --C(O)--. Such a group is the N terminal group is
present in Polymyxin B1 and Colistin A (i.e. where --X--R.sup.N
together are 6-methyloctanoyl).
[0563] In one embodiment, --R.sup.N is 5-methylhexyl, for example
where --X-- is --C(O)--. Such a group is the N terminal group is
present in Polymyxin B2 and Colistin B (i.e. where --X--R.sup.N
together are 6-methylheptanoyl).
[0564] In one embodiment, R.sup.N is heptyl, for example where
--X-- is --C(O)--. Such a group is the N terminal group is present
in Polymyxin B3 (i.e. where --X--R.sup.N together are 6-octanoyl).
In one embodiment, --R.sup.N is hexyl, for example where --X-- is
--C(O)--. Such a group is the N terminal group is present in
Polymyxin B4 (i.e. where --X--R.sup.N together are heptanoyl).
[0565] In one embodiment, --R.sup.N is diphenylmethyl, such as
4-phenylphenylmethyl.
[0566] In one embodiment, --R.sup.N is optionally substituted
C.sub.5-10 aryl.
[0567] In one embodiment, the optionally substituted C.sub.5-10
aryl is phenyl substituted with phenyl (i.e. biphenyl), for example
4-phenylphenyl or 2-phenylphenyl.
[0568] In one embodiment, --R.sup.N is phenyl or benzyl, where the
phenyl or benzyl is optionally substituted with one or more halo or
nitro groups.
[0569] In one embodiment, --R.sup.N is halophenyl, such as
chlorophenyl, such as 2-chlorophenyl for example where --X-- is
--NH(CO)--.
[0570] In one embodiment, --R.sup.N together with --X-- is not a
group R.sup.1 as described in WO 2015/149131, for example where
-A.sup.1- is L-Dap, L-Dab or L-Lys, -A.sup.2 is L-Thr, and
-A.sup.3- is L-Dap, L-Dab or L-Lys.
[0571] -A.sup.1-, -A.sup.2- and -A.sup.3 -
[0572] In one embodiment, -A.sup.1- is absent, and -A.sup.2- and
-A.sup.3- are present.
[0573] In one embodiment, -A.sup.1- and -A.sup.2- are absent, and
-A.sup.3- is present. Such a compound may be referred to as an
octapeptide.
[0574] In one embodiment, -A.sup.1-, -A.sup.2- and -A.sup.3- are
absent. Such a compound may be referred to as a heptapeptide.
[0575] Each of -A.sup.1-, -A.sup.2- and -A.sup.3- may be an
.alpha.-amino acid.
[0576] A reference to an .alpha.-amino acid includes proteinogenic
("natural") .alpha.-amino acids, optionally together with other
.alpha.-amino acids.
[0577] Examples of .alpha.-amino acids that are not proteinogenic
are those amino acids generated by post-translational modification,
or by other means. Examples include Dab, Dap, Dgp
(.alpha.,.beta.-diguanidinopropanoyl), ornithine and nor-valine
[0578] Also included are amino having a piperidine side chain that
is a gem di-substituent to the .alpha.-carbon. Thus the
.alpha.-carbon is a ring atom in the piperidine ring. This is a
cyclic analogue of Dab.
[0579] An amino acid, such as an .alpha.-amino acid, may be an L-
or D-amino acid. In one embodiment, each of -A.sup.1-, -A.sup.2-
and -A.sup.3-, where present, is an L-amino acid.
[0580] In one embodiment, where one or more of -A.sup.1-, -A.sup.2-
and -A.sup.3- is absent, and optionally where all of -A.sup.1-,
-A.sup.2- and -A.sup.3- are present, R.sup.T-X-- may be an
.alpha.-amino acid residue, such as an .alpha.-amino acid residue
selected from the group consisting of Ala, Ser, Thr, Val, Leu, Ile,
Pro, Phe, Tyr, Trp, His, Lys, Arg, .alpha.,.gamma.-diaminobutyric
acid (Dab) and .alpha.,.beta.-diaminopropionic acid (Dap).
[0581] In one embodiment, -A.sup.3- is an amino acid residue
represented by:
##STR00014## [0582] where the asterisk is the point of attachment
to -A.sup.2-, and --R.sup.3 corresponds to the side chain of an
amino acid at position 3 in the polymyxin compounds.
[0583] In one embodiment, the group --R.sup.3 together the carbonyl
group and nitrogen alpha to the carbon to which it is attached, is
an amino acid residue having an amino- and/or hydroxyl-containing
side chain. Thus, the group --R.sup.3 has amino and/or hydroxyl
functionality.
[0584] In one embodiment, for the compounds of formula (II) each of
-A.sup.1-, -A.sup.2- and -A.sup.3- has the same meaning as the
compounds of formula (I).
[0585] Protected Forms
[0586] Compounds of the invention, such as compounds of formula (I)
and (II), may be provided in a protected form. Here, reactive
functionality, such as amino functionality, may be masked in order
to prevent its reaction during a synthesis step. A protecting group
is provided to mask the reactive functionality, and this protecting
groups may be removed at a later stage of the synthesis to reveal
the original reactive functionality.
[0587] A compound of formula (Ia) is provided, and salts, solvates
and hydrates thereof, which is a compound of formula (I) in
protected form. For example, amino, hydroxyl, carboxyl and thiol
functionality present in compound (I) may be protected with a
protecting group, such as described herein. The compound of formula
(Ia) may be an intermediate for the preparation of the compound of
formula (I). Thus, compound (I) may be prepared from compound (la),
for example by removal of the protecting groups
("deprotection").
[0588] Similarly, a compound of formula (IIa) is provided, and
salts, solvates and hydrates thereof, which is a compound of
formula (II) in protected form. For example, amino, hydroxyl,
carboxyl and thiol functionality present in compound (II) may be
protected with a protecting group, such as described herein. The
compound of formula (IIa) may be an intermediate for the
preparation of the compound of formula (II). Thus, compound (II)
may be prepared from compound (IIa), for example by removal of the
protecting groups ("deprotection").
[0589] In one embodiment, the protected form is a compound where
amino, hydroxyl, thiol, and/or carboxyl functionality is protected
(masked) by a protecting group. In one embodiment, the protected
form is a compound where the side chain functionality of the amino
acids residues with the compound are protected.
[0590] In the compound of formula (I) and (II), the amino acid
residues at positions 5, 8 and 9 are Dab residues, and the side
chain of the Dab residue includes amino functionality. The amino
acid functionality of each Dab residue may be protected with an
amino protecting group, as described herein.
[0591] In certain embodiments of the invention, amino acid residue
-A.sup.3-, where present, is an amino acid residue where the side
chain includes amino functionality. Examples of -A.sup.3- include
Dab, a lysine residue, an ornithine residue, and Dap residues. The
amino functionality of these residues may be protected with an
amino protecting group, as described herein.
[0592] In certain embodiments of the invention, amino acid residue
-A.sup.3-, where present, is an amino acid residue where the side
chain includes hydroxyl functionality. Examples of -A.sup.3-
include serine and threonine residues. The hydroxyl functionality
of these residues may be protected with an hydroxyl protecting
group, as described herein.
[0593] In certain embodiments of the invention, amino acid residue
-A.sup.2-, where present, is an amino acid residue where the side
chain includes hydroxyl functionality. Examples of -A.sup.2-
include serine and threonine residues. The hydroxyl functionality
of these residues may be protected with an hydroxyl protecting
group, as described herein. In certain embodiments of the
invention, amino acid residue -A.sup.2-, where present, is an amino
acid residue where the side chain includes amino functionality. The
amino functionality of these residues may be protected with an
hydroxyl protecting group, as described herein.
[0594] In certain embodiments of the invention, amino acid residue
-A.sup.1-, where present, is an amino acid residue where the side
chain includes amino or hydroxyl functionality. Examples include
those amino acids mentioned above in relation to -A.sup.1-. These
functionalities may be protected with hydroxyl or amino protecting
groups, as described herein.
[0595] An amino acid reside, such as amino acid residue -A.sup.1-,
where present, may be an amino acid residue where the side chain
includes a nitrogen aromatic group, for example an imidazole group,
as found in a histidine residue. A nitrogen ring atom may be
protected with an amino protecting group as described herein.
[0596] An amino acid reside, such as amino acid residue -A.sup.1-,
where present, may be an amino acid residue where the side chain
includes carboxyl functionality. This functionality may be
protected with a carboxyl protecting group as described herein.
[0597] In certain embodiments of the invention, --R.sup.10 together
with the carbonyl group and nitrogen alpha to the carbon to which
it is attached is an amino acid residue where the side chain
includes hydroxyl functionality. An example of an amino acid
residue including --R.sup.10 is threonine. The hydroxyl
functionality of this residue may be protected with a hydroxyl
protecting group, as described herein.
[0598] In certain embodiments the --R.sup.T or --R.sup.N contains
functionality such as amino, hydroxyl carboxyl or thiol
functionality. The amino, hydroxyl carboxyl or thiol functionality
may be protected with amino, hydroxyl carboxyl or thiol protecting
groups, as described herein.
[0599] Protecting groups, such as those for amino acid residues,
are well known and well described in the art.
[0600] Amino acids having side group protection, optionally
together with amino and carboxy protection, are commercially
available. Thus, a protected polymyxin compound may be prepared
from appropriately protected amino acid starting materials.
[0601] Velkov et al. describe the step-wise preparation of
polymyxin compounds on the solid-phase using suitably protected
amino acid. The use of protected-forms of threonine and Dab is
disclosed (see Supplementary Information).
[0602] As noted above, however, Velkov et al. do not describe the
compounds of formula (II), for at least the reason that the amino
acid residues at position 6 are not exemplified in Velkov et
al.
[0603] Where a protecting group is used is it is removable under
conditions that do not substantially disrupt the structure of the
polymyxin core, for example conditions that do not alter the
stereochemistry of the amino acid residues.
[0604] In one embodiment, the protecting groups are acid-labile,
base labile, or are removable under reducing conditions.
[0605] Example protecting groups for amino functionality include
Boc (tert-butoxycabonyl), Bn (benzyl, Bzl), CbZ (Z), 2--CL-Z
(2-chloro), Dde
(1-[4,4-dimethyl-2,6-dioxocylcohex-1-ylidene]-3-methylbutyl), Fmoc
(fluorenylmethyloxycarbonyl), HSO.sub.3-Fmoc (sulfonylated Fmoc,
such as 2-sulfo-Fmoc, as described in e.g. Schechter et al, J. Med
Chem 2002, 45(19) 4264), ivDde
(1-[4,4-dimethyl-2,6-dioxocylcohex-1-ylidene]ethyl), Mmt
(4-methoxytrityl), Mtt (4-methyltrityl), Nvoc
(6-nitroveratroyloxycarbonyl), and Tfa (trifluroacetyl).
[0606] Example protecting groups for aromatic nitrogen
functionality includes Boc, Mtt, Trt and Dnp (dinitrophenyl).
[0607] In one embodiment, the protecting group for amino
functionality is selected from Boc, CbZ, Bn and Fmoc and
HSO.sub.3-Fmoc.
[0608] In one embodiment, the protecting group for amino
functionality is Boc, Fmoc or CbZ.
[0609] Example protecting groups for hydroxyl functionality include
Trt (trityl), Bn (benzyl), tBu (tert-butyl), and
2-acetamido-2-deoxy-3,4,6-tri-Oacetyl-.alpha.-galactopyranosyl.
[0610] In one embodiment, the protecting group for amino
functionality is Trt.
[0611] Further example protecting groups include silyl ether
protecting groups, such as TMS, TES, TBS, TIPS, TBDMS, and TBDPS.
Such protecting groups are removable with TBAF, for example.
[0612] Example protecting groups for carboxyl functionality include
Bn (benzyl, Bz), tBu (tert-butyl), TMSET (trimethylsilylethyl) and
Dmab
({[4,4-dimethyl-2,6-dioxocylcohex-1-ylidene]-3-methylbutyl}amino
benzyl).
[0613] Example protecting groups for aromatic nitrogen
functionality includes Boc, Mtt, Trt and Dnp (dinitrophenyl).
[0614] In some embodiments, only some types of functionality are
protected. For example, only amino groups may be protected, such as
amino groups in the side chain of an amino acid residue.
[0615] In one embodiment, amino groups and hydroxyl groups are
protected.
[0616] Log P
[0617] A compound of the invention, such as a compound of formula
(I) or (II), may have a partition-coefficient, such as expressed as
a Log P value, within certain limits. The partition-coefficient may
provide an indication of the lipophilicity of the compound.
[0618] A Log P value for a compound may be determined
experimentally (for example by partition of the compound between
octanol and water), or it may be predicted using standard
computational methods. For example, a reference to Log P may be a
reference to ALog P, which may be determined using the methods
described by Ghose et al. J. Phys. Chem. A, 1998, 102, 3762-3772,
the contents of which are hereby incorporated by reference in their
entirety. Thus, A Log P is the Ghose/Crippen group-contribution
estimate for Log P.
[0619] In one embodiment, a compound has a Log P value, such as an
A Log P value, of at least-3.0, at least-3.5, at least-4.0, at
least-6.0, at least-6.3, at least-6.5, at least-6.7, or at
least-7.0. In one embodiment, a compound has a Log P value, such as
an ALog P, value, of at most-2.0, at most-3.0, at most-3.5, at
most-4.0, at most-4.5, at most-5.0, at most-5.2, at most-5.5, or at
most-5.7.
[0620] In one embodiment, a compound has a Log P value within a
range having upper and lower limits appropriately selected from the
limits given above, for example within the range-5.0 to -6.3, such
as-5.5 to -6.3.
[0621] Compounds having Log P values, such as A Log P values,
within the limits discussed above are found to have excellent
activity against both polymyxin-susceptible and polymyxin-resistant
bacterial strains. Such compounds may also have reduced
cytotoxicity compared with polymyxin B.
[0622] In another embodiment, a compound has a Log P value within a
range having upper and lower limits selected from the limits given
above, for example within the range-2.0 to -4.0, such as -2.0 to
-3.5, such as-2.0 to -3.0.
[0623] Compounds having Log P values, such as A Log P values,
within the limits discussed above are found to have optimum
activity against polymyxin-resistant strains.
[0624] The present inventors have found that a compound having
suitable Log P values may be obtained by appropriate choice of N
terminal group (such as the choice of groups --R.sup.T or
--R.sup.N) and amino acid residues at position 6 and/or 7 (such as
with appropriate selection of --R.sup.6 and/or --R.sup.7).
[0625] Polymyxin B
[0626] The deacylated from of the Polymyxin B decapeptide has the
structure shown below:
##STR00015##
[0627] where positions 1, 2, 4, 6, 7 and 10 are indicated (with
reference to the standard numbering system used for the Polymyxin B
decapeptide), and the amino acid residues are in the
L-configuration, unless indicated.
[0628] Polymyxin B nonapeptide, octapeptides and heptapeptide forms
are also know in the art, and these compounds are truncated
versions of the decapeptide shown above
[0629] The compounds of the invention are variants of the polymyxin
B decapeptide, nonapeptide, octapeptides and heptapeptide, where
the amino acid at positions 6 and/or positions 7 is substituted
with another amino acid, as described herein, and optionally the
amino acid residues at positions 2, 3 and 10 are substituted with
another amino acid residue.
[0630] The compounds of formula (I) are compounds where the N
terminal group of the polypeptide (which may be a decapeptide, a
nonapeptide or other) is modified.
[0631] The compounds of formula (II) are compounds where the N
terminal amino group is optionally modified.
[0632] For convenience, the compounds of the invention are
represented by the formula (I) where the amino acids at positions
1, 2, 3, 6, 7 or 10 are determined by the nature of the groups
-A.sup.1-, -A.sup.2- and -A.sup.3-, --R.sup.6, --R.sup.7 and
--R.sup.10 respectively. Compounds of the invention, which include
the variants described above, are biologically active.
[0633] A variant of the compound is a compound in which one or
more, for example, from 1 to 5, such as 1, 2, 3 or 4 amino acids
are substituted by another amino acid. The amino acid may be at a
position selected from position 6 and/or 7 and optionally positions
1, 2, 3, and 10 (referring to the numbering of residues used in
polymyxin B). The substitution may be for another amino acid or for
a stereoisomer.
[0634] Methods of Preparation
[0635] Compounds of formula (I) and (II) be prepared by
conventional peptide synthesis, using methods known to those
skilled in the art. Suitable methods include solution-phase
synthesis such as described by Yamada et al, J. Peptide Res. 64,
2004, 43-50, or by solid-phase synthesis such as described by
Velkov et al., ACS Chemical Biology, 9, 2014, 1172 (including
Supplementary Information), de Visser et al., J. Peptide Res, 61,
2003, 298-306, and Vaara et al., Antimicrob. Agents and
Chemotherapy, 52, 2008. 3229-3236. These methods include a suitable
protection strategy, and methods for the cyclisation step.
[0636] As shown herein, it is possible to derivatise the N terminal
group of a deacylated polymyxin compound, such as deacylated
nonapeptides, without derivatising the amino groups that are
present in the side chains of the polymyxin compound. As described
herein, the side chains of the polymyxin compound may be
selectively protected without protecting the N terminal group. The
N terminal group may then be reacted to provide the appropriate N
terminal substituent. The side chain protection may subsequently be
removed.
[0637] The present inventors have also found that an amino acid at
position 6 or position 7 of a polymyxin compound may be modified in
a method of synthesis, thereby providing a product polymyxin having
a product having a modified amino acid.
[0638] The inventors have identified halogenated phenylalanine
amino acid residues are useful intermediates for the preparation of
modified amino acids. The halogen group is a useful reactive
functionality, and may be substituted for other groups, for example
in a cross-coupling reaction, such as a Suzuki-type cross-coupling
reaction with a boronic acid or ester, in the presence of a metal
catalyst.
[0639] The present invention provides a compound of formula (II)
where the amino acid residue at position 6 or position 7 contains a
halogenated phenyl group. However, the present invention is not
limited to the use of such compounds, and variants of compound of
formula (II) are also provided, and are useful in synthesis. For
example, the present invention also provides a compound of formula
(III), which comprises a halo aryl group.
[0640] In one embodiment, the method is the modification of
phenylalanine.
[0641] In one embodiment of the invention there is provided a
method of preparing a halogenated polymyxin compound, the method
comprising the step of treating a polymyxin compound with a
halogenating agent, thereby to provide the halogenated polymyxin
compound. Here, one the amino acid residue at position 6 or
position 7 contains an aryl group.
[0642] In one aspect there is provided a method of halogenating a
polymyxin compound comprising an aryl group, such as an aryl group
in an amino acid residue, the method comprising treating the
polymyxin compound with a halogenating agent. The product of the
reaction is a polymyxin compound containing a haloaryl group, such
as a haloaryl group in an amino acid residue. Such a compound may
be referred to as a halogenated polymyxin compound.
[0643] In one embodiment, the polymyxin compound comprises a
phenylalanine, tyrosine or histidine residue.
[0644] In one embodiment, the polymyxin compound comprises a
phenylalanine residue.
[0645] In one embodiment the method is the halogenation of a
polymyxin compound having a phenylalanine residue at position 6 or
position 7.
[0646] The phenyl group of a phenylalanine residue may be
halogenated at the 4-position or the 2-position, or the reaction
may produce a product having a mixture of the two. It is possible
to separate 2- and 4-halogenated products, for example by HPLC.
[0647] In one embodiment, the polymyxin compound comprises an
.alpha.-amino acid, where the side chain of the amino acid
comprises an aromatic group, such as a carboaryl group. In one
embodiment, the polymyxin compound comprises an .alpha.-amino acid,
where the side chain of the amino acid comprises a phenyl group,
which is optionally substituted. In one embodiment, the polymyxin
compound comprises an .alpha.-amino acid, where the side chain of
the amino acid comprises a benzyl group, which is optionally
substituted.
[0648] In one embodiment, there is provided a method for the
preparation of a polymyxin compound of formula (IV), the method
comprising the step of treating an aryl-containing polymyxin
compound of formula (III).
[0649] In one embodiment, the polymyxin compound of formula (III)
and (IV) is represented thus:
##STR00016##
[0650] wherein:
[0651] -T.sup.A is hydrogen, C.sub.1-4 alkyl or R.sup.N--X--;
[0652] -A.sup.1- is absent or is an amino acid residue;
[0653] -A.sup.2- is absent or is an amino acid residue;
[0654] -A.sup.3- is absent or is an amino acid residue;
[0655] --X-- is --C(O)--, --NHC(O)--, --OC(O)--, --CH.sub.2-- or
--SO.sub.2--;
[0656] --R.sup.N is a terminal group, such as a group --R.sup.T as
described herein;
[0657] --R.sup.6 together with the carbonyl group and nitrogen
alpha to the carbon to which it is attached is an amino acid
residue;
[0658] --R.sup.7 together with the carbonyl group and nitrogen
alpha to the carbon to which it is attached is an amino acid
residue;
[0659] and for the compounds of formula (IV) one of --R.sup.6 and
--R.sup.7, comprises a haloaryl group; and for the compounds of
formula (III) one of --R.sup.6 and --R.sup.7, comprises an aryl
group
[0660] R.sup.10 together with the carbonyl group and nitrogen alpha
to the carbon to which it is attached, is a threonine or leucine
residue;
[0661] and salts, solvates, and/or protected forms thereof.
[0662] In one embodiment, --R.sup.6 comprises a haloaryl or an aryl
group.
[0663] In one embodiment, --R.sup.7 comprises a haloaryl or an aryl
group.
[0664] In one embodiment, -A.sup.1-, -A.sup.2-, -A.sup.3- and
R.sup.N-- do not contain an optionally substituted aryl group.
[0665] In one embodiment, one of one of --R.sup.6 and --R.sup.7,
comprises a benzyl group, where the phenyl is substituted with
halo, such as monosubstituted.
[0666] In one embodiment, one of --R.sup.6 and --R.sup.7, comprises
a haloaryl group.
[0667] In one embodiment, one of --R.sup.6 and --R.sup.7, comprises
a bromoaryl group.
[0668] In one embodiment, the group --R.sup.N is as defined for the
compounds of formula (II).
[0669] In one embodiment, the polymyxin compound is Polymyxin B.
Thus, --X-- is --C(O)--, and --R.sup.N is selected from
5-methylheptyl, 5-methylhexyl, heptyl, and hexyl.
[0670] In one embodiment, the group --R.sup.N does not contain an
aryl group, for example does not contain a carboaryl or heteroaryl
group.
[0671] In one embodiment, --R.sup.6 is benzyl for the compounds of
formula (III), and --R.sup.6 is benzyl, where the phenyl group is
substituted at the 2- or 4- position with halo, such as bromo (for
the compounds of formula (IV)).
[0672] In one embodiment, the halogenation reaction is performed on
a polymyxin compound where the side chain functionality of the
amino acid residues and optionally the functionality within
--R.sup.N is not protected. The inventors have found that the
halogenation reaction may be advantageously performed directly on a
polymyxin starting material, without the need to protect the amino
acid functionality or protect functionality within --R.sup.N. Thus,
a halogenated product may be produced from a polymyxin starting
material in one step.
[0673] A halogenated polymyxin compound, such as compound (IV) may
be prepared without the need for protecting groups. After such a
compound is prepared ti may be necessary to protect the reactive
functionality for future syntheses.
[0674] The compound of formula (III) may be reacted with a
halogenating reagent to yield the compound of formula (IV).
[0675] In one embodiment, the halogenating reagent is a brominating
reagent, and the product of the reaction is a brominated
product.
[0676] In one embodiment, the halogenating reagent is
N-halosuccinimide
[0677] In one embodiment, the halogenating reagent is selected from
NBS (N-bromosuccinimide),
[0678] NCS (N-chlorosuccinimide), and NIS (N-iodosuccinimide).
[0679] In one embodiment, the halogenating reagent is NBS.
[0680] In one embodiment, the halogenating reagent is used in at
least 1 mole equivalent with respect to the mole amount of
aryl-containing compound.
[0681] In one embodiment, the halogenating reagent is used in at
most 2 moles equivalent with respect to the mole amount of
aryl-containing compound.
[0682] In one embodiment, the halogenating reagent is used at
around 1.5 moles equivalent with respect to the mole amount of
aryl-containing compound.
[0683] In one embodiment, the halogenating reagent is used together
with a Lewis acid.
[0684] In one embodiment, the Lewis acid is BF.sub.3.
[0685] In one embodiment, the Lewis acid is selected from
BF.sub.32H.sub.2O and BF.sub.3, 2AcOH, such as
[0686] BF.sub.3.2H.sub.2O.
[0687] The Lewis acid may be a solvent for the reaction.
[0688] Additionally or attentively, H2O, CH3CN, AcOH may be
present. Preferable no other solvent is present.
[0689] The halogenation reaction may be performed at ambient
temperature, or below. Typically the halogenation reaction is
performed at greater than 5.degree. C., as the preferred Lewis
acids crystallise at temperatures below 5.degree. C.
[0690] A halogenated polymyxin compound, such as compound (IV), is
suitable for use in methods of medical treatment as described
herein. A halogenated polymyxin compound is also suitable for use
as an intermediate in the preparation of alternative polymyxin
compounds, as described in further detail below.
[0691] In one aspect of the invention, there is provided a method
of synthesis, the method comprising the step of digesting a
halogenated polymyxin compound selected from a halogenated
decapeptide, a halogenated nonapeptide and a halogenated
octapeptide, thereby to yield a halogenated heptapeptide polymyxin
compound. Digesting refers to step of reducing the total number of
amino acid residues within a polypeptide.
[0692] In one embodiment, a compound of formula (IVa) is digested
to yield a compound of formula (IVb).
[0693] The compound of formula (IVa) is halogenated decapeptide, a
halogenated nonapeptide or a halogenated octapeptide. The compound
of formula (IVa) is a compound of formula (IV) where -A.sup.3- is
an amino acid residue. The compound of formula (IVa) is a compound
where --R.sup.6 or --R.sup.7 comprises a haloaryl group. Following
the cleavage reaction, the haloaryl group is retained in the
cleaved product.
[0694] The compound of formula (IVb) is a halogenated heptapeptide
polymyxin compound. The compound of formula (IVb) is a compound of
formula (IV) where -A.sup.1-, -A.sup.2-, and -A.sup.3- are absent
and --T.sup.A is hydrogen. Where the compound of formula (IVa) is a
compound where --R.sup.6 or --R.sup.7 comprises a haloaryl group,
it follows that the compound of formula (IVb) is a compound where
--R.sup.6 or --R.sup.7 comprises a haloaryl group.
[0695] In one embodiment a protease is used in the digestion
method, such as a serine protease, such as a subtilisin.
[0696] In one embodiment, Savinase is used to digest the
halogenated polymyxin compound.
[0697] The compound of formula (IVb) is a useful intermediate for
the preparation of polymyxin compounds. The compound of formula
(IVb) has an unmodified N terminal, and this terminal may be
functionalised. The compound of formula (IVb) also has a haloaryl
group, and the halogen may be substituted with another group to
give a substituted aryl group.
[0698] Accordingly, in one aspect there is provided a method of
synthesis, the method comprising the step of modifying the N
terminal of a halogenated heptapeptide polymyxin compound to yield
a halogenated polymyxin compound having a halogenated decapeptide,
a halogenated nonapeptide and a halogenated octapeptide, wherein
the N terminal of the halogenated decapeptide, a halogenated
nonapeptide and a halogenated octapeptides is optionally modified,
and a halogenated heptapeptide having a modified N terminal.
[0699] In one embodiment, the halogenated heptapeptide polymyxin
compound is a compound of formula (IVb). The product of the
reaction is a polymyxin compound of formula (V):
##STR00017##
[0700] wherein:
[0701] -T.sup.A is hydrogen, C.sub.1-4 alkyl or R.sup.N--X--;
[0702] -A.sup.1- is absent or is an amino acid residue;
[0703] -A.sup.2- is absent or is an amino acid residue;
[0704] -A.sup.3- is absent or is an amino acid residue; [0705] and
where -A.sup.1-, -A.sup.2-, and -A.sup.3- are absent, -T.sup.A is
C.sub.1-4 alkyl or R.sup.N--X--;
[0706] --X-- is --C(O)--, --NHC(O)--, --OC(O)--, --CH.sub.2-- or
--SO.sub.2--;
[0707] --R.sup.N is a terminal group, such as a group --R.sup.T as
described herein;
[0708] --R.sup.6 together with the carbonyl group and nitrogen
alpha to the carbon to which it is attached is an amino acid
residue;
[0709] --R.sup.7 together with the carbonyl group and nitrogen
alpha to the carbon to which it is attached is an amino acid
residue;
[0710] and one of --R.sup.6 and --R.sup.7, together with the
carbonyl group and nitrogen alpha to the carbon to which --R.sup.6
or --R.sup.7 is attached, is amino acid residue having a haloaryl
group;
[0711] R.sup.10 together with the carbonyl group and nitrogen alpha
to the carbon to which it is attached, is a threonine or leucine
residue;
[0712] and salts, solvates, and/or protected forms thereof.
[0713] The compound (V) is typically formed from (IVb) by an amide
coupling reaction. Thus, the terminal amino group in the compound
of formula (IVb) is reacted with an appropriate carboxylic acid
compound or activated carboxylic compound to yield the amide
product.
[0714] The carboxylic acid compound may be a compound of formula
(IVc):
##STR00018## [0715] where -A.sup.1-, -A.sup.2-, -A.sup.3- and
--T.sup.A have the same meanings as the compounds of formula (V),
and activated forms thereof.
[0716] In one embodiment, the reaction of a carboxylic acid with an
amine may be undertaken in the presence of one or more amide
coupling reagents, as are well known in the art. A coupling reagent
may optionally be used together with a base, such as an organic
base.
[0717] Amide coupling reagents suitable for use include
carbodiimides (e.g. EDC and DCC), phosphonium salts (e.g. PyBOP),
and uranium and guanidinium salts (e.g. HATU and HBTU), such as
described in further detail below.
[0718] A carbodiimide may include dicyclohexylcarbodiimide (DCC),
N-(3-dimethylaminopropyl)-N'-ethylcarbo-diimide (EDC),
1-tert-butyl-3-ethylcarbodiimide,
N-cyclohexyl-N'-2-morpholinoethyl)carbodiimide, and
diisopropylcarbodiimide.
[0719] A phosphonium salt may include
benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate
(PyBoP), (7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium
hexafluorophosphate (PyAOP) and chlorotripyrrolidinophosphonium
hexafluorophosphate (PyBroP).
[0720] Uranium and guanidinium salts include
O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HBTU),
O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TBTU),
O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU),
N,N,N',N'-tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate
(TSTU) and
O-[(ethoxycarbonyl)cyanomethylenamino]-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TNTU), amongst others.
[0721] Other agents may be used, including other
benzotriazole-containing agents such as N-hydroxybenzotriazole
(HOBt) and 1-hydroxy-7-azabenzotriazole (HOAt), or reagents such as
1-(mesitylene-2-sulfonyl)-3-nitro-1,2,4-triazole (MSNT) and
propylphosphonic anhydride (T3P).
[0722] Example coupling reagents are available from commercial
sources, for example as described in ChemFiles 2007, 4, No. 2,
Sigma-Aldrich.
[0723] As noted above, the reaction of the acid and the carboxylic
acid may be conducted in the presence of a base. Example bases
include alkylamine bases such as N,N-diisopropylethylamine (DIPEA)
and triethylamine (TEA), 4-dimethylaminopyridine (DMAP), pyridine,
and 4-methylmorpholine (NMM).
[0724] The amide-forming reaction may be performed in a solvent or
solvent mixture. A solvent for use may include dimethylformamide
(DMF) and dichloromethane (DCM), toluene and acetonitrile. Other
solvents, such as other alkyl formamides, halogenated hydrocarbons,
aromatic hydrocarbons and nitriles may be used as required.
[0725] The carboxylic acid compound used in the amide forming
reaction may be initially reacted with the amide coupling reagents
to pre-form an activated from of the carboxylic acid. The amine
compound may then be subsequently added to the reaction mixture.
This is not essential, and the reaction components may be mixed in
an alternative sequence, such as described in the worked examples
herein.
[0726] An activated form of the carboxylic acid includes an acyl
halide, a haloformate, an anhydride or a carboxylic ester. The
carboxylic acid may be reacted to form an acyl halide, haloformate,
anhydride or carboxylic ester by methods known in the art.
[0727] In one aspect of the invention, there is provided a method
of synthesis, the method comprising the step of substituting a
halogen within a halogenated polymyxin compound to yield a
polymyxin product having a substituted aromatic group. The
halogenated polymyxin compound is a compound having a haloaryl
group.
[0728] In one embodiment, the halogenated heptapeptide polymyxin
compound is a compound of formula (IV). The product of the reaction
is a polymyxin compound of formula (VI):
##STR00019##
[0729] wherein:
[0730] -T.sup.A is hydrogen, C.sub.1-4 alkyl or R.sup.N--X--;
[0731] -A.sup.1- is absent or is an amino acid residue;
[0732] -A.sup.2- is absent or is an amino acid residue;
[0733] -A.sup.3- is absent or is an amino acid residue; and where
-A.sup.1-, -A.sup.2-, and -A.sup.3- are absent, -T.sup.A is
C.sub.1-4 alkyl or R.sup.N--X--;
[0734] --X-- is --C(O)--, --NHC(O)--, --OC(O)--, --CH.sub.2-- or
--SO.sub.2--; --R.sup.N is a terminal group, such as a group
--R.sup.T as described herein;
[0735] --R.sup.6 together with the carbonyl group and nitrogen
alpha to the carbon to which it is attached is an amino acid
residue;
[0736] --R.sup.7 together with the carbonyl group and nitrogen
alpha to the carbon to which it is attached is an amino acid
residue;
[0737] and one of --R.sup.6 and --R.sup.7, comprises a substituted
aryl group;
[0738] R.sup.10 together with the carbonyl group and nitrogen alpha
to the carbon to which it is attached, is a threonine or leucine
residue;
[0739] and salts, solvates, and/or protected forms thereof.
[0740] In one embodiment, --R.sup.6 comprises a substituted aryl
group, such as a benzyl group.
[0741] In one embodiment, --R.sup.7 comprises a substituted aryl
group, such as a benzyl group.
[0742] The substitution reaction may be a cross-coupling
reaction.
[0743] The substitution reaction may be a metal-catalysed
substitution reaction.
[0744] The substitution reaction may be a Pd-catalysed substitution
reaction.
[0745] The substitution reaction may be a Suzuki-based coupling
(substitution) reaction. Thus, the haloaryl-containing polymyxin
compounds is reacted with a boronic acid or ester in the presence
of a metal catalyst to yield the substituted product.
[0746] In one embodiment, the substituted aryl group is aryl
substituted with --R.sup.F, where --R.sup.F is selected from
optionally substituted C.sub.1-12 alkyl, optionally substituted
C.sub.2-12 alkenyl, optionally substituted C.sub.2-12 alkynyl,
optionally substituted C.sub.3-10 cycloalkyl, optionally
substituted C.sub.3-10 heterocyclyl, optionally substituted
C.sub.5-12 aryl, and an optionally subsitued group may have one or
more substituent groups selected from halo, haloalkyl, alkyl,
alkenyl, alkynyl, and aryl, except that alkyl alkenyl, and alkynyl
groups are not substituents to the alkyl alkenyl, and alkynyl
groups. Suitable groups are described in relation to the definition
of --R.sup.P for --R.sup.6.
[0747] In one embodiment, the substituted aryl group is aryl
substituted with optionally substituted C.sub.5-12 aryl.
[0748] Thus, the substitution reaction involves the reaction of a
haloaryl groups with a reactive partner containing the group
--R.sup.F. For example, the reactive partner is a boronic acid or
ester comprising the group --R.sup.F.
[0749] A halogenated polymyxin compound having a modified N
terminal may be further reacted to yield a substituted polymyxin
compounds having a modified N terminal.
[0750] In one aspect of the invention, there is provided a method
of synthesis, the method comprising the step of substituting a
halogen within a halogenated polymyxin compound having a modified N
terminal to yield a polymyxin product having a modified N terminal
and a substituted aromatic group. The halogenated polymyxin
compound having a modified N terminal is a compound having an amino
acid residue with a haloaryl group.
[0751] The term "substituted" as used herein with reference to a
substitution reaction refers to the formal replacement of the
halogen group with another group (which may be a different type of
halogen group).
[0752] In one embodiment, the method is the replacement of the
halogen group with a different halogen group.
[0753] The methods of the reaction allow a commercially available
starting material or a naturally-produced starting material to be
converted to a compound of formula (I) or (II).
[0754] In a further aspect of the invention there is provided a
method of reducing an aryl-containing polymyxin compound, for
example a method or reducing a compound of formula (III) or (VI),
such as a protected form of (III) or (VI).
[0755] In one embodiment, the method comprises the step of
contacting a compound of formula (III) or (VI), or protected forms
thereof, with a metal catalyst in the present of hydrogen, thereby
to reduce the aryl group. The metal catalyst may be platinum
oxide.
[0756] Such methods are particularly useful for the preparation of
cyclohexyl-containing compounds from phenyl-containing compounds,
as exemplified herein.
[0757] Active Agent
[0758] The compounds of formula (I) or (II) may each be used
together with a second agent. The inventors have found that such
combinations have greater biological activity than would be
expected from the individual activity of both compounds. The
compounds of formula (I) or (II) can be used to potentiate the
activity of the second agent. In particular, the compounds of
formula (I) or (II) may be used together with a second agent to
enhance the antimicrobial activity of that agent, for example
against Gram-negative bacteria.
[0759] Without wishing to be bound by theory it is believed that
the compounds of formula (I) or (II) act on the outer membrane of a
cell e.g. a Gram-negative bacterial cell, to facilitate the uptake
of the second agent into that cell. Thus, agents that are otherwise
incapable or poor at crossing the outer membrane may be taken up
into a target cell by the action of the compounds of formula (I) or
(II).
[0760] In one embodiment, the combination of a compound of formula
(I) or (II) with the second agent is active against Gram-negative
bacteria. Here, it is not essential that individually either of the
compound of formula (I) or (II) or the second agent have activity
against Gram-negative bacteria.
[0761] In one embodiment, the second agent is an agent having a
measured MIC value against a particular microorganism, such as a
bacterium, that is less than 10, less than 5, or less than 1
micrograms/mL. The microorganism may be a Gram-negative bacteria,
such as a Gram-negative bacteria selected from the group consisting
of E. coli, S. enterica, K. pneumoniae, K. oxytoca; E. cloacae, E.
aerogenes, E. agglomerans, A. calcoaceticus, A. baumannii;
Pseudomonas aeruginosa, Stenotrophomonas maltophila, Providencia
stuartii, P. mirabilis, and P. vulgaris.
[0762] Examples of second agents that have activity against
Gram-negative bacteria include beta-lactams, tetracyclines,
aminoglycosides and quinolones.
[0763] In one embodiment, the second agent is an agent having a
measured MIC value against a particular microorganism, such as a
Gram-negative bacterium, that is more than 4, more than 8, more
than 16 or more than 32 micrograms/mL. In this embodiment, the
second agent may be active against Gram-positive bacteria. For
example, the second agent is an agent having a measured MIC value
against a particular Gram-positive bacterium that is less than 10,
less than 5, or less than 1 micrograms/mL. Here, the compound of
formula (I) or (II) acts to facilitate the uptake of the second
agent into the Gram-negative bacterial cell. The second agent is
therefore able to act on a target within the Gram-negative
bacterial cell, which target may be the same as the second agent's
target in a Gram-positive bacterial cell.
[0764] The Gram-positive bacteria may be selected from the group
consisting of Staphylococcus and Streptococcus bacteria, such as S.
aureus (including MRSA), S. epidermis, E. faecalis, and E.
faecium.
[0765] Examples of second agents that have activity against
Gram-positive bacteria (at the MIC values given above, for
example), and moderate activity against Gram-negative bacteria,
include rifampicin, novobiocin, macrolides, pleuromutilins. In one
embodiment, a compound having moderate activity against
Gram-negative bacteria may have a measured MIC value against a
Gram-negative bacterium that is less than 32, less than 64, or less
than 128 micrograms/mL.
[0766] Also suitable for use are agents having activity against
Gram-positive bacteria and which are essentially inactive against
Gram-negative bacteria. Examples include fusidic acid,
oxazolidinines (e.g. linezolid), glycopeptides (e.g. vancomycin),
daptomycin and Iantibiotics. In one embodiment, a compound having
essentially no activity against Gram-negative bacteria may have a
measured MIC value against a Gram-negative bacterium that is more
than 32, more then 64, more than 128, more than 256
micrograms/mL.
[0767] Under normal circumstances such agents are not necessarily
suitable for use against Gram-negative bacteria owing to their
relatively poor ability to cross the outer membrane of a
Gram-negative bacterial cell. As explained above, when used
together with a compound of formula (I) or (II), such agents are
suitable for use.
[0768] In one embodiment, the active agent may be selected from the
group consisting of rifampicin (rifampin), rifabutin, rifalazil,
rifapentine, rifaximin, aztreonam, oxacillin, novobiocin, fusidic
acid, azithromycin, ciprofloxacin, meropenem, tigecycline,
erythromycin, clarithromycin and mupirocin, and pharmaceutically
acceptable salts, solvates and prodrug forms thereof.
[0769] The present inventors have found that the polymyxin
compounds of formula (I) or (II) may be used together with certain
compounds in the rifamycin family to treat microbial infections.
The rifamycin family includes isolates rifamycin A, B, C, D, E, S
and SV, and synthetically derivatised versions of these compounds,
such as rifampicin (rifampin), rifabutin, rifalazil, rifapentine,
and rifaximin, and pharmaceutically acceptable salts and solvates
thereof. In one embodiment, the active agent is rifampicin
(rifampin) and pharmaceutically acceptable salts, solvates and
prodrug forms thereof.
[0770] Salts, Solvates and Other Forms
[0771] Examples of salts of compound of formula (I) and (II)
include all pharmaceutically acceptable salts, such as, without
limitation, acid addition salts of strong mineral acids such as HCl
and HBr salts and addition salts of strong organic acids such as a
methanesulfonic acid salt. Further examples of salts include
sulphates and acetates such as trifluoroacetate or
trichloroacetate.
[0772] In one embodiment the compounds of the present disclosure
are provided as a sulphate salt or a trifluoroacetic acid (TFA)
salt. In one embodiment the compounds of the present disclosure are
provided as acetate salts.
[0773] A compound of formula (I) or (II) can also be formulated as
prodrug. Prodrugs can include an antibacterial compound herein
described in which one or more amino groups are protected with a
group which can be cleaved in vivo, to liberate the biologically
active compound. In one embodiment the prodrug is an "amine
prodrug". Examples of amine prodrugs include sulphomethyl, as
described in e.g., Bergen et al, Antimicrob. Agents and
Chemotherapy, 2006, 50, 1953 or HSO3-FMOC, as described in e.g.
Schechter et al, J. Med Chem 2002, 45(19) 4264, and salts thereof.
Further examples of amine prodrugs are given by Krise and Oliyai in
Biotechnology: Pharmaceutical Aspects, 2007, 5(2), 101-131.
[0774] In one embodiment a compound of formula (I) or (II) is
provided as a prodrug.
[0775] A reference to a compound of formula (I) or (II), or any
other compound described herein, is also a reference to a solvate
of that compound. Examples of solvates include hydrates.
[0776] A compound of formula (I) or (II), or any other compound
described herein, includes a compound where an atom is replaced by
a naturally occurring or non-naturally occurring isotope. In one
embodiment the isotope is a stable isotope. Thus a compound
described here includes, for example deuterium containing compounds
and the like. For example, H may be in any isotopic form, including
.sup.1H, .sup.2H (D), and .sup.3H (T); C may be in any isotopic
form, including .sup.12C, .sup.13C, and .sup.14C; O may be in any
isotopic form, including .sup.16O and .sup.18O; and the like.
[0777] Certain compounds of formula (I) or (II), or any other
compound described herein, may exist in one or more particular
geometric, optical, enantiomeric, diasteriomeric, epimeric,
atropic, stereoisomeric, tautomeric, conformational, or anomeric
forms, including but not limited to, cis- and trans-forms; E- and
Z-forms; c-, t-, and r- forms; endo- and exo-forms; R--, S--, and
meso-forms; D- and L-forms; d- and I-forms; (+) and (-) forms;
keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal-
and anticlinal-forms; .alpha.- and .beta.-forms; axial and
equatorial forms; boat-, chair-, twist-, envelope-, and
halfchair-forms; and combinations thereof, hereinafter collectively
referred to as "isomers" (or "isomeric forms").
[0778] Note that, except as discussed below for tautomeric forms,
specifically excluded from the term "isomers," as used herein, are
structural (or constitutional) isomers (i.e., isomers which differ
in the connections between atoms rather than merely by the position
of atoms in space). For example, a reference to a methoxy group,
--OCH.sub.3, is not to be construed as a reference to its
structural isomer, a hydroxymethyl group, --CH.sub.2OH. Similarly,
a reference to ortho-chlorophenyl is not to be construed as a
reference to its structural isomer, meta-chlorophenyl. However, a
reference to a class of structures may well include structurally
isomeric forms falling within that class (e.g., C.sub.1-6alkyl
includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-,
and tert-butyl; methoxyphenyl includes ortho-, meta-, and
para-methoxyphenyl).
[0779] Unless otherwise specified, a reference to a particular
compound includes all such isomeric forms, including mixtures
(e.g., racemic mixtures) thereof. Methods for the preparation
(e.g., asymmetric synthesis) and separation (e.g., fractional
crystallisation and chromatographic means) of such isomeric forms
are either known in the art or are readily obtained by adapting the
methods taught herein, or known methods, in a known manner.
[0780] One aspect of the present invention pertains to compounds in
substantially purified form and/or in a form substantially free
from contaminants.
[0781] In one embodiment, the substantially purified form is at
least 50% by weight, e.g., at least 60% by weight, e.g., at least
70% by weight, e.g., at least 80% by weight, e.g., at least 90% by
weight, e.g., at least 95% by weight, e.g., at least 97% by weight,
e.g., at least 98% by weight, e.g., at least 99% by weight.
[0782] Unless specified, the substantially purified form refers to
the compound in any stereoisomeric or enantiomeric form. For
example, in one embodiment, the substantially purified form refers
to a mixture of stereoisomers, i.e., purified with respect to other
compounds. In one embodiment, the substantially purified form
refers to one stereoisomer, e.g., optically pure stereoisomer. In
one embodiment, the substantially purified form refers to a mixture
of enantiomers. In one embodiment, the substantially purified form
refers to an equimolar mixture of enantiomers (i.e., a racemic
mixture, a racemate). In one embodiment, the substantially purified
form refers to one enantiomer, e.g., optically pure enantiomer.
[0783] In one embodiment, the contaminants represent no more than
50% by weight, e.g., no more than 40% by weight, e.g., no more than
30% by weight, e.g., no more than 20% by weight, e.g., no more than
10% by weight, e.g., no more than 5% by weight, e.g., no more than
3% by weight, e.g., no more than 2% by weight, e.g., no more than
1% by weight.
[0784] Unless specified, the contaminants refer to other compounds,
that is, other than stereoisomers or enantiomers. In one
embodiment, the contaminants refer to other compounds and other
stereoisomers. In one embodiment, the contaminants refer to other
compounds and the other enantiomer.
[0785] In one embodiment, the substantially purified form is at
least 60% optically pure (i.e., 60% of the compound, on a molar
basis, is the desired stereoisomer or enantiomer, and 40% is the
undesired stereoisomer or enantiomer), e.g., at least 70% optically
pure, e.g., at least 80% optically pure, e.g., at least 90%
optically pure, e.g., at least 95% optically pure, e.g., at least
97% optically pure, e.g., at least 98% optically pure, e.g., at
least 99% optically pure.
[0786] Methods of Treatment
[0787] The compounds of formula (I) or (II), or pharmaceutical
formulations containing these compounds, are suitable for use in
methods of treatment and prophylaxis. The compounds may be
administered to a subject in need thereof. The compounds are
suitable for use together with an active agent ("a second active
agent"), for example a second active agent that is an antimicrobial
agent.
[0788] The compounds of formula (I) or (II) are for use in a method
of treatment of the human or animal body by therapy. In some
aspects of the invention, a compound of formula (I) or (II) may be
administered to a mammalian subject, such as a human, in order to
treat a microbial infection.
[0789] Another aspect of the present invention pertains to use of a
compound of formula (I) or (II) in the manufacture of a medicament
for use in treatment. In one embodiment, the medicament comprises a
compound of formula (I) or (II). In one embodiment, the medicament
is for use in the treatment of a microbial infection.
[0790] The term "microbial infection" refers to the invasion of the
host animal by pathogenic microbes. This includes the excessive
growth of microbes that are normally present in or on the body of
an animal. More generally, a microbial infection can be any
situation in which the presence of a microbial population(s) is
damaging to a host animal. Thus, an animal is "suffering" from a
microbial infection when excessive numbers of a microbial
population are present in or on an animal's body, or when the
presence of a microbial population(s) is damaging the cells or
other tissue of an animal.
[0791] The compounds may be used to treat a subject having a
microbial infection, or at risk of infection from a microorganism,
such as a bacterium.
[0792] The microbial infection may be a bacterial infection such as
a Gram-negative bacterial infection.
[0793] Examples of Gram-negative bacteria include, but are not
limited to, Escherichia spp., Klebsiella spp., Enterobacter spp.,
Salmonella spp., Shigella spp., Citrobacter spp., Morganella
morganii, Yersinia pseudotuberculosis and other Enterobacteriaceae,
Pseudomonas spp., Acinetobacter spp., Moraxella, Helicobacter,
Stenotrophomonas, Bdellovibrio, acetic acid bacteria, Legionella
and alpha-proteobacteria such as Wolbachia and numerous others.
[0794] Medically relevant Gram-negative cocci include three
organisms, which cause a sexually transmitted disease (Neisseria
gonorrhoeae), a meningitis (Neisseria meningitidis), and
respiratory symptoms (Moraxella catarrhalis).
[0795] Medically relevant Gram-negative bacilli include a multitude
of species. Some of them primarily cause respiratory problems
(Hemophilus influenzae, Klebsiella pneumoniae, Legionella
pneumophila, Pseudomonas aeruginosa), primarily urinary problems
(Escherichia coli, Enterobacter cloacae), and primarily
gastrointestinal problems (Helicobacter pylori, Salmonella
enterica).
[0796] Gram-negative bacteria associated with nosocomial infections
include Acinetobacter baumannii, which causes bacteremia, secondary
meningitis, and ventilator-associated pneumonia in intensive-care
units of hospital establishments.
[0797] In one embodiment the Gram-negative bacterial species is
selected from the group consisting of E. coli, S. enterica, K.
pneumoniae, K. oxytoca; E. cloacae, E. aerogenes, E. agglomerans,
A. calcoaceticus, A. baumannii; Pseudomonas aeruginosa,
Stenotrophomonas maltophila, Providencia stuartii, P. mirabilis,
and P. vulgaris.
[0798] In one embodiment the Gram-negative bacterial species is
selected from the group consisting of E. colt, K. pneumoniae,
Pseudomonas aeruginosa, and A. baumannii.
[0799] The compounds of formula (I) or (II) or compositions
comprising the same are useful for the treatment of skin and soft
tissue infections, gastrointestinal infection, urinary tract
infection, pneumonia, sepsis, intra-abdominal infection and
obstetrical/gynaecological infections. The infections may be
Gram-positive or Gram-negative bacterial infections.
[0800] The compounds of formula (I) or (II) or compositions
comprising the same are useful for the treatment of Pseudomonas
infections including P. aeruginosa infection, for example skin and
soft tissue infections, gastrointestinal infection, urinary tract
infection, pneumonia and sepsis.
[0801] The compounds of formula (I) or (II) or compositions
comprising the same are useful for the treatment of Acinetobacter
infections including A. baumanii infection, for pneumonia, urinary
tract infection and sepsis.
[0802] The compounds of formula (I) or (II) or compositions
comprising the same are useful for the treatment of Klebsiella
infections including K. pneumoniae infection, for pneumonia,
urinary tract infection, meningitis and sepsis.
[0803] The compounds of formula (I) or (II) or compositions
comprising the same are useful for the treatment of E. coli
infection including E. coli infections, for bacteremia,
cholecystitis, cholangitis, urinary tract infection, neonatal
meningitis and pneumonia.
[0804] The active agent may be an agent that has activity against
the microorganism. The active agent may be active against
Gram-negative bacteria. The active agent may be active against a
microorganism selected from the list given above.
[0805] In one embodiment, the second active agent has an MIC value
of 10 micrograms/mL or less against a microorganism such as E.
coli, in the absence of the compound of formula (I) or (II). The
microorganism may be a microorganism selected from the group
above.
[0806] Specific compounds for use as second active agents are
described herein and include: [0807] rifampicin, rifabutin,
rifalazil, rifapentine, and rifaximin; [0808] oxacillin,
methicillin, ampicillin, cloxacillin, carbenicillin, piperacillin,
tricarcillin, flucloxacillin, and nafcillin; [0809] azithromycin,
clarithromycin, erythromycin, telithromycin, cethromycin, and
solithromycin; [0810] aztreonam and BAL30072; [0811] meropenem,
doripenem, imipenem, ertapenem, biapenem, tomopenem, and panipenem;
[0812] tigecycline, omadacycline, eravacycline, doxycycline, and
minocycline; [0813] ciprofloxacin, levofloxacin, moxifloxacin, and
delafloxacin; [0814] Fusidic acid; [0815] Novobiocin; [0816]
teichoplanin, telavancin, dalbavancin, and oritavancin, and
pharmaceutically acceptable salts and solvates thereof;
[0817] In one embodiment, specific compounds for use as second
active agents are described herein and include rifampicin
(rifampin), rifabutin, rifalazil, rifapentine, rifaximin,
aztreonam, oxacillin, novobiocin, fusidic acid, azithromycin,
ciprofloxacin, meropenem, tigecycline, erythromycin, clarithromycin
and mupirocin, and pharmaceutically acceptable salts and solvates
thereof.
[0818] In an alternative aspect, the compounds of formula (I) are
suitable for use in the treatment of fungal infections, for example
in combination together with an antifungal agent. The antifungal
agent may be selected from a polyene antifungal, for example
amphotericin B, an imidazole, triazole, or thiazole antifungal, for
example micaonazole, fluconazole or abafungin, an allylamine, an
echinocandin, or another agent, for example ciclopirox.
[0819] Treatment
[0820] The term "treatment," as used herein in the context of
treating a condition, pertains generally to treatment and therapy,
whether of a human or an animal (e.g., in veterinary applications),
in which some desired therapeutic effect is achieved, for example,
the inhibition of the progress of the condition, and includes a
reduction in the rate of progress, a halt in the rate of progress,
alleviation of symptoms of the condition, amelioration of the
condition, and cure of the condition. Treatment as a prophylactic
measure (i.e., prophylaxis) is also included. For example, use with
patients who have not yet developed the condition, but who are at
risk of developing the condition, is encompassed by the term
"treatment."
[0821] The term "therapeutically-effective amount," as used herein,
pertains to that amount of a compound, or a material, composition
or dosage form comprising a compound, which is effective for
producing some desired therapeutic effect, commensurate with a
reasonable benefit/risk ratio, when administered in accordance with
a desired treatment regimen.
[0822] The term "treatment" includes combination treatments and
therapies, as described herein, in which two or more treatments or
therapies are combined, for example, sequentially or
simultaneously.
[0823] Combination Therapy
[0824] A compound of formula (I) or (II) may be administered in
conjunction with an active agent.
[0825] Administration may be simultaneous, separate or
sequential.
[0826] The methods and manner of administration will depend on the
pharmacokinetics of the compound of formula (I) or (II) and the
second agent.
[0827] By "simultaneous" administration, it is meant that a
compound of formula (I) or (II) and a second agent are administered
to a subject in a single dose by the same route of
administration.
[0828] By "separate" administration, it is meant that a compound of
formula (I) or (II) and a second agent are administered to a
subject by two different routes of administration which occur at
the same time. This may occur for example where one agent is
administered by infusion and the other is given orally during the
course of the infusion.
[0829] By "sequential" it is meant that the two agents are
administered at different points in time, provided that the
activity of the first administered agent is present and ongoing in
the subject at the time the second agent is administered.
[0830] Generally, a sequential dose will occur such that the second
of the two agents is administered within 48 hours, preferably
within 24 hours, such as within 12, 6, 4, 2 or 1 hour(s) of the
first agent. Alternatively, the active agent may be administered
first, followed by the compound of formula (I) or (II).
[0831] Ultimately, the order and timing of the administration of
the compound and second agent in the combination treatment will
depend upon the pharmacokinetic properties of each.
[0832] The amount of the compound of formula (I) or (II) to be
administered to a subject will ultimately depend upon the nature of
the subject and the disease to be treated. Likewise, the amount of
the active agent to be administered to a subject will ultimately
depend upon the nature of the subject and the disease to be
treated.
[0833] Formulations
[0834] In one aspect, the present invention provides a
pharmaceutical composition comprising a compound of formula (I) or
(II) together with a pharmaceutically acceptable carrier. The
pharmaceutical composition may additionally comprise a second
active agent. In an alternative embodiment, where a second agent is
provided for use in therapy, the second agent may be separately
formulated from the compound of formula (I) or (II). The comments
below made in relation to the compound of formula (I) or (II) may
therefore also apply to the second agent, as separately
formulated.
[0835] While it is possible for the compound of formula (I) or (II)
to be administered alone or together with the second agent, it is
preferable to present it as a pharmaceutical formulation (e.g.,
composition, preparation, medicament) comprising at least one
compound of formula (I) or (II), as described herein, together with
one or more other pharmaceutically acceptable ingredients well
known to those skilled in the art, including, but not limited to,
pharmaceutically acceptable carriers, diluents, excipients,
adjuvants, fillers, buffers, preservatives, anti-oxidants,
lubricants, stabilisers, solubilisers, surfactants (e.g., wetting
agents), masking agents, colouring agents, flavouring agents, and
sweetening agents. The formulation may further comprise other
active agents, for example, other therapeutic or prophylactic
agents.
[0836] Thus, the present invention further provides pharmaceutical
compositions, as defined above, and methods of making a
pharmaceutical composition comprising admixing at least one
compound of formula (I) or (II), as described herein, together with
one or more other pharmaceutically acceptable ingredients well
known to those skilled in the art, e.g., carriers, diluents,
excipients, etc. If formulated as discrete units (e.g., tablets,
etc.), each unit contains a predetermined amount (dosage) of the
compound. The composition optionally further comprises the second
active agent in a predetermined amount.
[0837] The term "pharmaceutically acceptable," as used herein,
pertains to compounds, ingredients, materials, compositions, dosage
forms, etc., which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of the subject in
question (e.g., human) without excessive toxicity, irritation,
allergic response, or other problem or complication, commensurate
with a reasonable benefit/risk ratio. Each carrier, diluent,
excipient, etc. must also be "acceptable" in the sense of being
compatible with the other ingredients of the formulation.
[0838] Suitable carriers, diluents, excipients, etc. can be found
in standard pharmaceutical texts, for example, Remington's
Pharmaceutical Sciences, 18th edition, Mack Publishing Company,
Easton, Pa., 1990; and Handbook of Pharmaceutical Excipients, 5th
edition, 2005.
[0839] The formulations may be prepared by any methods well known
in the art of pharmacy. Such methods include the step of bringing
into association the compound of formula (I) or (II) with a carrier
which constitutes one or more accessory ingredients. In general,
the formulations are prepared by uniformly and intimately bringing
into association the compound with carriers (e.g., liquid carriers,
finely divided solid carrier, etc.), and then shaping the product,
if necessary.
[0840] The formulation may be prepared to provide for rapid or slow
release; immediate, delayed, timed, or sustained release; or a
combination thereof.
[0841] Formulations may suitably be in the form of liquids,
solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous,
non-aqueous), emulsions (e.g., oil-in-water, water-in-oil),
elixirs, syrups, electuaries, mouthwashes, drops, tablets
(including, e.g., coated tablets), granules, powders, losenges,
pastilles, capsules (including, e.g., hard and soft gelatin
capsules), cachets, pills, ampoules, boluses, suppositories,
pessaries, tinctures, gels, pastes, ointments, creams, lotions,
oils, foams, sprays, mists, or aerosols.
[0842] Formulations may suitably be provided as a patch, adhesive
plaster, bandage, dressing, or the like which is impregnated with
one or more compounds and optionally one or more other
pharmaceutically acceptable ingredients, including, for example,
penetration, permeation, and absorption enhancers. Formulations may
also suitably be provided in the form of a depot or reservoir.
[0843] The compound may be dissolved in, suspended in, or admixed
with one or more other pharmaceutically acceptable ingredients. The
compound may be presented in a liposome or other microparticulate
which is designed to target the compound, for example, to blood
components or one or more organs. Where a liposome is used, it is
noted that the liposome may contain both the compound of formula
(I) or (II) and the second agent.
[0844] Formulations suitable for oral administration (e.g., by
ingestion) include liquids, solutions (e.g., aqueous, non-aqueous),
suspensions (e.g., aqueous, non-aqueous), emulsions (e.g.,
oil-in-water, water-in-oil), elixirs, syrups, electuaries, tablets,
granules, powders, capsules, cachets, pills, ampoules, boluses.
[0845] Formulations suitable for buccal administration include
mouthwashes, losenges, pastilles, as well as patches, adhesive
plasters, depots, and reservoirs. Losenges typically comprise the
compound in a flavoured basis, usually sucrose and acacia or
tragacanth. Pastilles typically comprise the compound in an inert
matrix, such as gelatin and glycerin, or sucrose and acacia.
Mouthwashes typically comprise the compound in a suitable liquid
carrier.
[0846] Formulations suitable for sublingual administration include
tablets, losenges, pastilles, capsules, and pills.
[0847] Formulations suitable for oral transmucosal administration
include liquids, solutions (e.g., aqueous, non-aqueous),
suspensions (e.g., aqueous, non-aqueous), emulsions (e.g.,
oil-in-water, water-in-oil), mouthwashes, losenges, pastilles, as
well as patches, adhesive plasters, depots, and reservoirs.
[0848] Formulations suitable for non-oral transmucosal
administration include liquids, solutions (e.g., aqueous,
non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions
(e.g., oil-in-water, water-in-oil), suppositories, pessaries, gels,
pastes, ointments, creams, lotions, oils, as well as patches,
adhesive plasters, depots, and reservoirs.
[0849] Formulations suitable for transdermal administration include
gels, pastes, ointments, creams, lotions, and oils, as well as
patches, adhesive plasters, bandages, dressings, depots, and
reservoirs.
[0850] Tablets may be made by conventional means, e.g., compression
or moulding, optionally with one or more accessory ingredients.
Compressed tablets may be prepared by compressing in a suitable
machine the compound in a free-flowing form such as a powder or
granules, optionally mixed with one or more binders (e.g.,
povidone, gelatin, acacia, sorbitol, tragacanth,
hydroxypropylmethyl cellulose); fillers or diluents (e.g., lactose,
microcrystalline cellulose, calcium hydrogen phosphate); lubricants
(e.g., magnesium stearate, talc, silica); disintegrants (e.g.,
sodium starch glycolate, cross-linked povidone, cross-linked sodium
carboxymethyl cellulose); surface-active or dispersing or wetting
agents (e.g., sodium lauryl sulfate); preservatives (e.g., methyl
p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid);
flavours, flavour enhancing agents, and sweeteners. Moulded tablets
may be made by moulding in a suitable machine a mixture of the
powdered compound moistened with an inert liquid diluent. The
tablets may optionally be coated or scored and may be formulated so
as to provide slow or controlled release of the compound therein
using, for example, hydroxypropylmethyl cellulose in varying
proportions to provide the desired release profile. Tablets may
optionally be provided with a coating, for example, to affect
release, for example an enteric coating, to provide release in
parts of the gut other than the stomach.
[0851] Ointments are typically prepared from the compound and a
paraffinic or a water-miscible ointment base.
[0852] Creams are typically prepared from the compound and an
oil-in-water cream base. If desired, the aqueous phase of the cream
base may include, for example, at least about 30% w/w of a
polyhydric alcohol, i.e., an alcohol having two or more hydroxyl
groups such as propylene glycol, butane-1,3-diol, mannitol,
sorbitol, glycerol and polyethylene glycol and mixtures thereof.
The topical formulations may desirably include a compound which
enhances absorption or penetration of the compound through the skin
or other affected areas. Examples of such dermal penetration
enhancers include dimethylsulfoxide and related analogues.
[0853] Emulsions are typically prepared from the compound and an
oily phase, which may optionally comprise merely an emulsifier
(otherwise known as an emulgent), or it may comprises a mixture of
at least one emulsifier with a fat or an oil or with both a fat and
an oil. Preferably, a hydrophilic emulsifier is included together
with a lipophilic emulsifier which acts as a stabiliser. It is also
preferred to include both an oil and a fat. Together, the
emulsifier(s) with or without stabiliser(s) make up the so-called
emulsifying wax, and the wax together with the oil and/or fat make
up the so-called emulsifying ointment base which forms the oily
dispersed phase of the cream formulations.
[0854] Suitable emulgents and emulsion stabilisers include Tween
60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl
monostearate and sodium lauryl sulfate. The choice of suitable oils
or fats for the formulation is based on achieving the desired
cosmetic properties, since the solubility of the compound in most
oils likely to be used in pharmaceutical emulsion formulations may
be very low. Thus the cream should preferably be a non-greasy,
non-staining and washable product with suitable consistency to
avoid leakage from tubes or other containers. Straight or branched
chain, mono- or dibasic alkyl esters such as di-isoadipate,
isocetyl stearate, propylene glycol diester of coconut fatty acids,
isopropyl myristate, decyl oleate, isopropyl palmitate, butyl
stearate, 2-ethylhexyl palmitate or a blend of branched chain
esters known as Crodamol CAP may be used, the last three being
preferred esters. These may be used alone or in combination
depending on the properties required. Alternatively, high melting
point lipids such as white soft paraffin and/or liquid paraffin or
other mineral oils can be used.
[0855] Formulations suitable for intranasal administration, where
the carrier is a liquid, include, for example, nasal spray, nasal
drops, or by aerosol administration by nebuliser, include aqueous
or oily solutions of the compound. As an alternative method of
administration, a dry powder delivery may be used as an alternative
to nebulised aerosols.
[0856] Formulations suitable for intranasal administration, where
the carrier is a solid, include, for example, those presented as a
coarse powder having a particle size, for example, in the range of
about 20 to about 500 microns which is administered in the manner
in which snuff is taken, i.e., by rapid inhalation through the
nasal passage from a container of the powder held close up to the
nose.
[0857] Formulations suitable for pulmonary administration (e.g., by
inhalation or insufflation therapy) include those presented as an
aerosol spray from a pressurised pack, with the use of a suitable
propellant, such as dichlorodifluoromethane,
trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide,
or other suitable gases. Additionally or alternatively, a
formulaton for pulmonary administration may be formulated for
administration from a nebuliser or a dry powder inhaler. For
example, the formulation may be provided with carriers or liposomes
to provide a suitable particle size to reach the appropriate parts
of the lung, to aid delivery of an appropriate does to enhance
retention in the lung tissue.
[0858] Formulations suitable for ocular administration include eye
drops wherein the compound is dissolved or suspended in a suitable
carrier, especially an aqueous solvent for the compound.
[0859] Formulations suitable for rectal administration may be
presented as a suppository with a suitable base comprising, for
example, natural or hardened oils, waxes, fats, semi-liquid or
liquid polyols, for example, cocoa butter or a salicylate; or as a
solution or suspension for treatment by enema.
[0860] Formulations suitable for vaginal administration may be
presented as pessaries, tampons, creams, gels, pastes, foams or
spray formulations containing in addition to the compound, such
carriers as are known in the art to be appropriate.
[0861] Formulations suitable for parenteral administration (e.g.,
by injection), include aqueous or non-aqueous, isotonic,
pyrogen-free, sterile liquids (e.g., solutions, suspensions), in
which the compound is dissolved, suspended, or otherwise provided
(e.g., in a liposome or other microparticulate). Such liquids may
additional contain other pharmaceutically acceptable ingredients,
such as anti-oxidants, buffers, preservatives, stabilisers,
bacteriostats, suspending agents, thickening agents, and solutes
which render the formulation isotonic with the blood (or other
relevant bodily fluid) of the intended recipient. Examples of
excipients include, for example, water, alcohols, polyols,
glycerol, vegetable oils, and the like. Examples of suitable
isotonic carriers for use in such formulations include Sodium
Chloride Injection, Ringer's Solution, or Lactated Ringer's
Injection. Typically, the concentration of the compound in the
liquid is from about 1 ng/mL to about 100 .mu.g/mL, for example
from about 10 ng/mL to about 10 .mu.g/mL, for example from about 10
ng/mL to about 1 .mu.g/mL. The formulations may be presented in
unit-dose or multi-dose sealed containers, for example, ampoules
and vials, and may be stored in a freeze-dried (lyophilised)
condition requiring only the addition of the sterile liquid
carrier, for example water for injections, immediately prior to
use. Extemporaneous injection solutions and suspensions may be
prepared from sterile powders, granules, and tablets.
[0862] Dosage
[0863] Generally, the methods of the invention may comprise
administering to a subject an effective amount of a compound of
formula (I) or (II) so as to provide an antimicrobial effect. The
compound of formula (I) or (II) may be administered at an amount
sufficient to potentiate the activity of a second active agent. The
second active agent is administered to a subject at an effective
amount so as to provide an antimicrobial effect.
[0864] It will be appreciated by one of skill in the art that
appropriate dosages of the compound of formula (I) or (II) or the
active agent, and compositions comprising the compound of formula
(I) or (II) or the active agent, can vary from patient to patient.
Determining the optimal dosage will generally involve the balancing
of the level of therapeutic benefit against any risk or deleterious
side effects. The selected dosage level will depend on a variety of
factors including, but not limited to, the activity of the
particular compound of formula (I) or (II) or the active agent, the
route of administration, the time of administration, the rate of
excretion of the compound, the duration of the treatment, other
drugs, compounds, and/or materials used in combination, the
severity of the condition, and the species, sex, age, weight,
condition, general health, and prior medical history of the
patient. The amount of compound of formula (I) or (II) or the
active agent and route of administration will ultimately be at the
discretion of the physician, veterinarian, or clinician, although
generally the dosage will be selected to achieve local
concentrations at the site of action which achieve the desired
effect without causing substantial harmful or deleterious
side-effects.
[0865] Administration can be effected in one dose, continuously or
intermittently (e.g., in divided doses at appropriate intervals)
throughout the course of treatment. Methods of determining the most
effective means and dosage of administration are well known to
those of skill in the art and will vary with the formulation used
for therapy, the purpose of the therapy, the target cell(s) being
treated, and the subject being treated. Single or multiple
administrations can be carried out with the dose level and pattern
being selected by the treating physician, veterinarian, or
clinician.
[0866] In general, a suitable dose of a compound of formula (I) or
(II) or the active agent is in the range of about 10 .mu.g to about
250 mg (more typically about 100 .mu.g to about 25 mg) per kilogram
body weight of the subject per day. Where the compound of formula
(I) or (II) or the active agent is a salt, an ester, an amide, a
prodrug, or the like, the amount administered is calculated on the
basis of the parent compound and so the actual weight to be used is
increased proportionately.
[0867] Kits
[0868] One aspect of the invention pertains to a kit comprising (a)
a compound of formula (I) or (II), or a composition comprising a
compound as defined in any one of formula (I) or (II), e.g.,
preferably provided in a suitable container and/or with suitable
packaging; and (b) instructions for use, e.g., written instructions
on how to administer the compound or composition.
[0869] The written instructions may also include a list of
indications for which the compound of formula (I) or (II) is a
suitable treatment.
[0870] In one embodiment, the kit further comprises (c) a second
active agent, or a composition comprising the second active agent.
Here, the written instructions may also include a list of
indications for which the second active agent, together with the
compound of formula (I) or (II), is suitable for treatment.
[0871] Routes of Administration
[0872] A compound of formula (I) or (II), a second agent, or a
pharmaceutical composition comprising the compound of formula (I)
or (II), or the second agent may be administered to a subject by
any convenient route of administration, whether
systemically/peripherally or topically (i.e., at the site of
desired action).
[0873] Routes of administration include, but are not limited to,
oral (e.g., by ingestion); buccal; sublingual; transdermal
(including, e.g., by a patch, plaster, etc.); transmucosal
(including, e.g., by a patch, plaster, etc.); intranasal (e.g., by
nasal spray); ocular (e.g., by eyedrops); pulmonary (e.g., by
inhalation or insufflation therapy using, e.g., via an aerosol,
e.g., through the mouth or nose); rectal (e.g., by suppository or
enema); vaginal (e.g., by pessary); parenteral, for example, by
injection, including subcutaneous, intradermal, intramuscular,
intravenous, intraarterial, intracardiac, intrathecal, intraspinal,
intracapsular, subcapsular, intraorbital, intraperitoneal,
intratracheal, subcuticular, intraarticular, subarachnoid, and
intrasternal; by implant of a depot or reservoir, for example,
subcutaneously or intramuscularly.
[0874] The Subject/Patient
[0875] The subject/patient may be a chordate, a vertebrate, a
mammal, a placental mammal, a marsupial (e.g., kangaroo, wombat), a
rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine
(e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a
bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a
horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g.,
a cow), a primate, simian (e.g., a monkey or ape), a monkey (e.g.,
marmoset, baboon), an ape (e.g., gorilla, chimpanzee, orang-utan,
gibbon), or a human. Furthermore, the subject/patient may be any of
its forms of development, for example, a foetus.
[0876] In one preferred embodiment, the subject/patient is a
human.
[0877] It is also envisaged that the invention may be practised on
a non-human animal having a microbial infection. A non-human mammal
may be a rodent. Rodents include rats, mice, guinea pigs,
chinchillas and other similarly-sized small rodents used in
laboratory research.
[0878] Other Preferences
[0879] Each and every compatible combination of the embodiments
described above is explicitly disclosed herein, as if each and
every combination was individually and explicitly recited.
[0880] Various further aspects and embodiments of the present
invention will be apparent to those skilled in the art in view of
the present disclosure.
[0881] "and/or" where used herein is to be taken as specific
disclosure of each of the two specified features or components with
or without the other. For example "A and/or B" is to be taken as
specific disclosure of each of (i) A, (ii) B and (iii) A and B,
just as if each is set out individually herein.
[0882] Unless context dictates otherwise, the descriptions and
definitions of the features set out above are not limited to any
particular aspect or embodiment of the invention and apply equally
to all aspects and embodiments which are described. Where
technically appropriate embodiments may be combined and thus the
disclosure extends to all permutations and combinations of the
embodiments provided herein.
[0883] Certain aspects and embodiments of the invention will now be
illustrated by way of example and with reference to the figures
described above.
Examples
[0884] The following examples are provided solely to illustrate the
present invention and are not intended to limit the scope of the
invention, as described herein.
[0885] Nomenclature--Compounds are named based on the natural
polymyxin core from which they are synthetically derived.
TABLE-US-00001 Abbreviation Meaning PMBN Polymyxin B nonapeptide
PMB Polymyxin B Thr Threonine Ser Serine DSer D-serine Leu Leucine
Ile Isoleucine Phe Phenylalanine Dphe D-phenylalanine Val Valine
Dab .alpha.,.gamma.-Diaminobutyric acid DIPEA
N,N-diisopropylethylamine HATU 2-(7-aza-1H-benzotriazol-1-yl)-
1,1-3,3-tetramethyluronium hexafluorophosphate DCM Dichloromethane
TFA Trifluoroacetic acid ND Not determined N/A Not applicable DMF
N,N-Dimethylformamide PMBH Polymyxin B heptapeptide (3-10) PMBD
Polymyxin B decapepide Pro Proline Dap
.alpha.,.beta.-Diaminopropionic acid Gly Glycine His Histidine Phe
Phenylalanine DCHA Dicyclohexylamine X phos
2-Dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl NorLeu
Norleucine NorVal Norvaline OctGly Octyl glycine
Synthesis Examples
[0886] Comparator compounds C1 to C3 were prepared. Polymyxin B has
a D-phenylalanine residue at position 6. The N terminal group is a
6-methyloctanoyl group. Polymyxin B is readily available.
[0887] Compounds C1 and C2 have previously been prepared by the
present inventors. These compounds are polymyxin B nonapeptide
derivatives. The compounds have a D-phenylalanine residue at
position 6. The N terminal of the amino acid reside at position 2
is modified, as shown. The preparation of these compounds is
described herein and is described in GB 1404301.2.
[0888] Compound C3 is a Polymyxin B variant differing from
Polymyxin B in the substitution of the phenylalanine residue at
position 6 with a D-(biphenyl)alanine residue (a
D-(4-phenylphenyl)alanine residue). Compound C3 is structurally
related close to the variants described by Velkov et al. C3 shares
the same N terminal group as Polymyxin B (specifically Polymyxin
B1), whilst Velkov et al. describes modified N terminal group.
Compound C.sub.3 may be prepared by the methods described in Velkov
et al. with appropriate replacement of the fatty acid in the
terminal coupling step (see the Supporting Information for this
paper).
[0889] In each of the worked examples 1-26, the amino acid at
position 6 is replaced with another amino acid. In some examples
the amino acid residue at position 1 is deleted, and the N terminal
of the amino acid residue at position 2 is modified, as shown.
[0890] Additional example compounds 27-79 are also provided, where
the the amino acid at position 6 is replaced with another amino
acid. In some examples the amino acid residue at position 1 is
deleted, and the N terminal of the amino acid residue at position 2
is modified, as shown.
[0891] Additionally comparator compounds C4 to C7 were
prepared.
[0892] The compounds for use in the present case are prepared as
described below. Each of the compounds has a polymyxin heptapeptide
core (save for the amino acid at position 6 or position 7). The
compounds possess an L-Thr residue at the position corresponding to
position 2 in polymyxin and an L-Dab or an L-Dap residue at the
position corresponding to position 3 in polymyxin (where L-Thr and
L-Dab are the natural amino acid residues present at these
positions within Polymyxin B).
[0893] The compounds of the invention may be prepared by adaptation
of the detailed methods described below, and may also be prepared
by adaptation of the methods described in WO 2015/135976, the
contents of which are hereby incorporated by reference in their
entirety. The methods used in the present case also include those
of WO 2013/072695 and WO 2014/188178, the contents of which are
hereby incorporated by reference in their entirety.
[0894] The compounds of the present invention differ from the
compounds of WO 2015/135976 in the nature of the amino acid
residues at positions 6 and/or 7 (i.e. in the nature of the groups
--R.sup.6, --R.sup.6a, --R.sup.7, and --R.sup.7a). However, the N
terminal groups of the compounds of WO 2015/135976 are suitable for
use in the compounds of the invention. Thus a group --R.sup.T or a
group --R.sup.N in the compounds of formula (I) or (II) of the
present case may be a group --R.sup.15 as described in WO
2015/135976.
[0895] Therefore the description and exemplification of N terminal
modifications in WO 2015/135976 is relevant to the work in the
present case. WO 2015/135976 shows that certain N terminal groups
provide enhanced antibacterial activity and/or reduced cytotoxicity
compared with wild type Polymyxin B (for example). Such N terminal
groups may be used together with the amino acid substitutions at
positions 6 and/or 7, as described by the inventors in the present
case.
[0896] In particular, the present case incorporates by reference
the detailed synthesis examples of WO 2015/135976 from page 65 to
page 90 (which examples are also present in GB 1421020.7 and GB
1516059.1, to which the present case claims priority).
[0897] Intermediate 5-Tri-(Boc) Polymyxin B heptapeptide
[0898] PMB sulphate (2 g) was dissolved in water (20 mL) followed
by addition of 1,4-dioxane (40 mL) and left to stir for 10 minutes
at room temperature. To the reaction mixture was added Boc
anhydride (4.42 g) was added as solid and the reaction was stirred
at room temperature and was monitored by HPLC. The reaction mixture
was then adjusted to pH 6 using 1 M HCl , the precipitate which
formed was filtered and washed with water (50 mL) and heptane (50
mL), to leave Boc.sub.5PMB as a white solid (2.4 g, 85%). This
material (1 g) was dissolved in 1,4-butanediol (112.5 mL) and the
mixture was stirred at 40.degree. C. overnight. To the solution
potassium phosphate (75 mL, 0.12 5M pH 8.0) was added over one
minute, causing the formation of a white suspension. The reaction
was diluted by adding 112.5 mL butanediol and 75 mL potassium
phosphate (0.125 M pH 8.0), but the white emulsion persisted. The
temperature of the reaction was reduced to 37.degree. C. and then
Savinase 16L (250 .mu.L) was added and the reaction was stirred at
room temperature overnight. As the reaction progressed the white
emulsion cleared to form a transparent solution due to the
formation of the more soluble PMBH-Boc.sub.3. The reaction mixture
was diluted with water (50 ml) and was then extracted with DCM (100
mL) The DCM layer was collected and evaporated in vacuo to afford a
colourless oil. The resulting oil was diluted in 50% methanol (aq.)
and was loaded onto four preconditioned 10 g Varian Bond Elut SCX
cartridges and the flow through was collected. The cartridges were
washed with two column volumes of 50% methanol (aq.) and then
PMBH-Boc.sub.3 was eluted from the column using two column volumes
of 20% ammonia in methanol. The resulting eluent was evaporated to
dryness in vacuo to afford purified PMBH-Boc.sub.3 (610 mg). m/z
1062.6 [M+H].sup.+.
[0899] Intermediate 7- Thr(O-.sup.tBu) Tetra-(N-Boc) Polymyxin B
nonapeptide
[0900] Step 1-
(S)-2-((S)-2-Benzyloxycarbonylamino-3-tert-butoxy-butyrylamino)-4-tert-bu-
toxycarbonylamino-butyric acid methyl ester
[0901] To a stirred suspension of
(S)-2-Benzyloxycarbonylamino-3-tert-butoxy-butyric acid DHCA salt
(3.65 g, 7.4 mmol) and
(S)-2-Amino-4-tert-butoxycarbonylamino-butyric acid methyl ester
HCl salt (2.0 g, 7.4 mmol) in a mixture of DCM (60 mL) and DMF (120
mL) was added N,N-diisopropylethylamine (3.85 mL, 22.1 mmol). To
this stirred mixture was added 1-hydroxy-7-azabenzotriazole (1.0 g,
7.3 mmol) followed by
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide HCl salt (1.42 g,
7.4 mmol). The mixture was stirred for 17 h at ambient temperature
then filtered under suction to remove the insoluble by-product,
which was discarded. The filtrate was concentrated to a yellow oil
which was partitioned between a solvent mixture of EtOAc/Et.sub.2O
(1:1) (250 mL) and 0.5 M hydrochloric acid (200 mL). The aqueous
phase was re-extracted with fresh solvent mixture (100 mL) and the
combined organic extracts were successively washed with water (150
mL) and sat. NaHCO.sub.3 solution (150 mL), dried
(Na.sub.2SO.sub.4) and concentrated to a colourless oil (3.72g).
This oil was purified by silica gel chromatography on a 100g SepPak
cartridge, eluting with a solvent gradient of EtOAc/i-hexane
(0-70%). Fractions containing the product (R.sub.f 0.26 in
EtOAc/i-hexane 3:7, visualized with KMnO.sub.4 spray) were pooled
and concentrated to give the title compound as a colourless foam
(3.58 g, 6.8 mmol, 92% yield). m/z 524 (MH.sup.+, 100%).
[0902] Step 2-
(S)-2-((S)-2-Benzyloxycarbonylamino-3-tert-butoxy-butyrylamino)-4-tert-bu-
toxycarbonylamino-butyric acid
[0903] A solution of lithium hydroxide monohydrate (0.861 g, 20.5
mmol) in water (16 mL) was added to a stirred solution of
(S)-2-((S)-2-Benzyloxycarbonylamino-3-tert-butoxy-butyrylamino)-4-tert-bu-
toxycarbonylamino-butyric acid methyl ester (3.58 g, 6.8 mmol) in
methanol (64 mL) at ambient temperature and stirred for 19 h. To
this solution was added 1M HCl (24 mL) resulting in a milky mixture
(pH 1) which was quickly extracted with DCM (3.times.135 mL). The
combined organic extract was dried (Na.sub.2SO.sub.4) and
concentrated to give the title compound as a colourless foam (3.27
g, 6.4 mmol, 94% yield).M/z 532[MNa]+, 1041 [2M+Na]+.
[0904] Step 3-CbzHNPMBN(OBu)(Boc).sub.4
[0905] (S)-2-((S)-2-Benzyloxycarbonylam
ino-3-tert-butoxy-butyrylami no)-4-tert-butoxycarbonylam
ino-butyric acid (1.73 g, 3.39 mmol) and Tri-(N-Boc) Polymyxin B
heptapeptide (prepared according to WO 2012/168820, 3.0 g, 2.8
mmol) were charged to a flask to which dry DCM (85 ml) and dry DMF
(17 mL) were added with stirring. To the stirred solution was added
N,N-diisopropylethylamine (1.46 ml, 8.4 mmol) and after stirring
for 5 min., O-(7-azabenzotriazol -1-yl)-N,N,N'N'-tetramethyluronium
hexafluorophosphate (1.29 g, 3.39 mmol) was added in a single
portion. The mixture was sonicated for 2 minutes then left to stir
at ambient temperature for 18 h. The reaction mixture was then
evaporated and the residue re-evaporated from toluene (3.times.100
mL). The residue was dried under vacuum for 3 h to ensure removal
of toluene. Water (50 ml) was added to this material and the
mixture was rapidly stirred for 3 h with occasional sonication. The
title compound was collected by suction filtration as a fine, white
solid and washed with water (2.times.25 mL) then dried under vacuum
for 15h (4.6 g, 3.0 mmol, 100% yield). m/z 1554[MH+].
[0906] Step 4-Title Compound
[0907] The product from step 3 (5.41 g, 3.48 mmol), ammonium
formate (6.6 g, 104.4 mmol) and 10% Pd--C (2.0 g) were charged to a
flask under N2. MeOH (270 mL) was added and the mixture was stirred
under N.sub.2 for 4.5h. LCMS showed MH.sup.+ for product and loss
of starting material. The mixture was filtered under suction
through a pad of celite and washed through with MeOH (50 mL). The
filtrate and washings were evaporated to a colourless oil which was
partitioned between a solvent mixture of EtOAc/MeOH (4:1)(250 mL)
and water (250 mL). The aqueous phase was further extracted with
the same, fresh solvent mixture (2.times.100 mL). The combined
organic extracts were dried (Na.sub.2SO.sub.4) and evaporated to a
colourless oil (.about.6 g). This material was purified by
chromatography on silica gel (100 g SepPak column) eluting with a
gradient of MeOH/EtOAc (0-4%). Fractions containing the product (Rf
0.30 in EtOAc/MeOH/NH.sub.4OH.sub.88095:5:1, visualized with
KMnO.sub.4 spray) were pooled and evaporated to give the title
compound as a crispy foam (4.0 g, 2.8mmol, 81% yield). m/z 1420
[MH+].
[0908] Intermediate 11- Tetra-
(N-Boc)-L-Thr(O-.sup.tBu)-L-Dap-Polymyxin B heptapeptide
[0909] The title compound was prepared from
(S)-2-((S)-2-Benzyloxycarbonylamino-3-tert-butoxy-butyrylamino)-3-tert-bu-
toxycarbonylamino-propionic acid and Intermediate 5 according to
the method for Intermediate 7 steps 3 and 4. m/z 1405,
[MH].sup.+
[0910] Intermediate 16 (BOC).sub.3 D-[(4-Bromo)Phe]-6-Polymyxin
heptapeptide and
[0911] Intermediate 17 (BOC).sub.3 D-[(2-Bromo)Phe]-6-Polymyxin
heptapeptide
[0912] Step 1-D-[(4-Bromo)Phe]-6-Polymyxin and
D-[(2-Bromo)Phe]-6-Polymyxin
##STR00020##
[0913] Polymyxin B sulphate (source: Biotika) (20.0 g, 15.4 mmol)
and N-bromosuccinimide (4.2 g, 23.6 mmol) were charged to a 1 L
3-neck round-bottomed flask, fitted with an efficient overhead
paddle stirrer and a N.sub.2 inlet. To the flask under N.sub.2 was
added boron trifluoride dihydrate (200 mL) and the mixture was
vigorously stirred at ambient temperature for 1 h during which time
all solids dissolved to give a frothy, orange solution. The
solution was then poured over 5 minutes into a stirred mixture of
ammonia 880 solution (400 mL) and ice (900 g) to give a white
suspension. To the suspension (pH 9) was added water (300 mL) and
the mixture was stirred at ambient temperature for 2h then filtered
under suction through a large (20 cm diameter, porosity 2) glass
sinter funnel. The solid was washed with water (200 mL) and sucked
free of excessive moisture. The material was then suspended in
methanol (1.5 L) and re-evaporated to a residue. This was repeated
with more methanol (1.5 L) to afford a foam which was dried at
ambient temperature in vacuo for 3h (22.4 g) and identified as the
title compound m/z=1282/4 (MH.sup.+), 643 (M+2H).sup.2+. The crude
material was used without purification in the next stage.
[0914] An aliquot was purified by preparative HPLC using the
conditions of General method 1, to afford Example Compound 2 (data
in Table)
[0915] Step 2-(Boc).sub.5 D-[(4-Bromo)Phe]-6-Polymyxin
##STR00021##
[0916] Crude D-[(4-Bromo)Phe]-6-Polymyxin (15.4 mmol nominal
amount, based on Polymyxin B sulphate used) was charged to a flask
and acetonitrile (400 mL) and water (200 mL) were added. To the
stirred solution was added triethylamine (15 mL, 108 mmol),
followed by a solution of di-tert-butyl-dicarbonate (23.5 g, 108
mmol) in acetonitrile (200 mL). The cloudy mixture was stirred at
ambient temperature for 20 h. The reaction mixture was then
concentrated in vacuo and the residue re-evaporated from methanol
(1 L) and dried. The dry residue was stirred with a mixture of
diethyl ether (75 mL) and iso-hexane (75 mL) for 0.5 h and the
insoluble solid was filtered off under vacuum. The solid was
partitioned between dichloromethane/methanol (9:1) (400 mL) and 10%
brine (300 mL). To the organic extract was added methanol (40 mL)
and the solution was washed with 10% brine (100 mL), dried
(Na.sub.2SO.sub.4) and concentrated in vacuo to a foam residue.
This material was suspended in dichloromethane/methanol (95:5) (140
mL) and left to stand for 0.5h. The mixture was filtered under
suction to remove unwanted gelatinous solid and the filtrate was
purified by column chromatography over silica gel, eluting with a
gradient of dichloromethane/methanol to afford the title compound
as a colourless foam (5.1 g) m/z 1782/4 (MH.sup.+). This partly
purified material was used directly in the next stage.
[0917] Step 3-(BOC).sub.3 D-[(4-Bromo)Phe]-6-Polymyxin heptapeptide
and (BOC).sub.3 D-[(2-Bromo)Phe]-6-Polymyxin heptapeptide
##STR00022##
[0918] A suspension of crude (Boc).sub.5
D-[(4-Bromo)Phe]-6-Polymyxin (2.65 g, 1.49 mmol) in 1,4-butanediol
(76 mL) was stirred at 50.degree. C. for 1h until a thick solution
was formed. Phosphate buffer solution (pH 8) (19 mL) was added and
the stirred solution was cooled to 37.degree. C. Savinase solution
(Protease from Bacillus sp. Liquid>16 U/g, from Sigma Aldrich)
(3 ml) was added and the viscous solution was stirred at 37.degree.
C. for 4 days. The solution was poured into a mixture of ethyl
acetate (150 mL) and water (100 mL) and the whole was shaken
vigorous. The aqueous layer was re-extracted with ethyl acetate (50
mL) and the combined organic extracts were re-washed with water
(2.times.75 mL), dried (Na.sub.2SO.sub.4) and evaporated in vacuo
to afford an oil (1.94 g). This material was dissolved in ethyl
acetate/methanol (4:1) (10 mL) and the solution purified by column
chromatography over silica gel eluting with a gradient of Solvent
A/ethyl acetate (0-60%) where Solvent A=methanol/ammonia 880
solution (9:1). Relevant fractions were pooled and evaporated to a
colourless foam (970 mg) identified as the title compound m/z
1140/2 (MH.sup.+).
[0919] Further purification by preparative HPLC (see Table A,
General Method 1) afforded the pure title compound Intermediate 16,
(BOC)3 D-[(4-Bromo)Phe]-6-Polymyxin heptapeptide and Intermediate
17, D-[(2-Bromo)Phe]-6-Polymyxin heptapeptide. m/z 1140/2
(MH.sup.+).
[0920] Intermediate 18-
(Cbz)(BOC).sub.4Thr(O.sup.1Bu)-D-[(4-Bromo)Phe]-6-PMB
nonapeptide
[0921] Prepared from Intermediate 16 and
(S)-2-((S)-2-Benzyloxycarbonylamino-3-tert-butoxy-butyrylamino)-4-tert-bu-
toxycarbonylamino-butyric acid using the method of Intermediate 7
step 3., to afford the title compound m/z 1633 (MH.sup.+).
[0922] Intermediate 19-(BOC).sub.4 Thr(OtBu)-L-Dap-(D--Cha-6)-PMB
heptapeptide
##STR00023##
[0923] Platinum oxide (200 mg) was added to a solution of
tetra-(N-Boc)-L-Thr(O-.sup.tBu)-L-Dap-Polymyxin B heptapeptide
(Intermediate 11) (1.8 g, 1.28 mmol) in acetic acid (80 mL).
Hydrogen gas was introduced and the reaction was stirred for 24
hours. Platinum oxide (400 mg) was added and the reaction stirred
under hydrogen for a further 48 hours. The solvent was evaporated
and the crude material was azeotroped with toluene (2.times.). The
crude oil was dissolved in EtOAc and then treated with Ambersep 900
(OH) resin. The resin was filtered off, washed with further EtOAc
(2.times.) and the combined organics were evaporated to afford the
title compound as an off-white solid (1.76 g). MH.sup.+=1412.0,
C.sub.66H.sub.118N.sub.14O.sub.19 requires 1411.7.
[0924] Intermediate 20-(BOC).sub.4 Thr(O.sup.1Bu)-(D-Cha-6)-PMB
nonapeptide
[0925] Prepared from Intermediate 7 (Thr(O-.sup.tBu) Tetra-(N-Boc)
Polymyxin B nonapeptide) using the conditions described above for
the preparation of Intermediate 19, to afford the title compound,
MH.sup.+=1425.6, C.sub.67H.sub.120N.sub.14O.sub.19 requires
1425.8.
[0926] General method 1: Preparation of nonapeptide amides
[0927] Step 1-The protected polymyxin nonapeptide (0.07 mmol) was
dissolved in dichloromethane (4 mL), and treated with the
corresponding carboxylic acid (1.5 equiv. with respect to the
polymyxin substrate), N,N-Diisopropylethylamine (3.0 equiv.),
followed by HATU (2.0 equivalent). After 16 h the completion of the
reaction was confirmed by LC-MS and the reaction mixture was
evaporated to dryness. Water (.about.10 mL) was added and the
mixture triturated then stirred vigorously for 1 h. The resultant
precipitate was collected by filtration and dried in vacuo
overnight.
[0928] Step 2 -The Boc-protected derivative from Step 1 was
dissolved in dichloromethane (3 mL) and treated with TFA (1 mL).
The reaction mixture was stirred at room temperature until LCMS
confirmed complete deprotection. The solvent was evaporated and the
residue chromatographed by preparative HPLC using the conditions in
Table A:
TABLE-US-00002 TABLE A Prep HPLC conditions Column: Sunfire C18 OBD
5 .mu.m .times. 30 mm .times. 150 mm Mobile Phase A: Acetonitrile +
0.15% TFA Mobile Phase B: water + 0.15% TFA Flow rate: 25 mL/min
Gradient: Time 0 min 3% A 97% B Time 2 min 3% A 97% B Time 25 min
40% A 60% B Time 30 min 97% A 3% B Time 32 min 97% A 3% B
Detection: 210 nm
[0929] Product-containing fractions were combined, evaporated to
low volume, and lyophilised to afford the product as the TFA salt.
Compound purity was assessed by HPLC using the conditions outlined
in Table B.
TABLE-US-00003 TABLE B Analytical HPLC conditions Column: Zorbax 5
.mu. C18 (2) 150 .times. 4.6 mm Mobile Phase A: 10% Acetonitrile in
90% Water, 0.15% TFA Mobile Phase B: 90% Acetonitrile in 10% Water,
0.15% TFA Flow rate: 1 mL/min Gradient: Time 0 min 100% A 0% B Time
10 min 0% A 100% B Time 11 min 0% A 100% B Time 11.2 min 100% A 0%
B Cycle time 15 min Injection volume: 20 .mu.L Detection: 210
nm
General method 2: General method for the preparation of dipeptide
amide derivatives of polymyxin B heptapeptide
[0930] In an alternative method, the carboxylic acid was coupled to
a suitably protected amino acid methyl ester using HATU coupling
conditions of Intermediate 1 step 3. The methyl ester was
hydrolysed as in Intermediate 1 step 2, then coupled to a suitably
protected amino acid methyl ester using HATU coupling conditions of
Intermediate 7 step 1. After ester hydrolysis (Intermediate 7 step
2) , the acyl dipeptide was coupled to the required polymyxin
heptapeptide intermediate followed by deprotection, as described in
General Method 1, to afford the example compounds.
[0931] General method 3: Suzuki Coupling Method
[0932] Exemplified by the synthesis of (Cbz)(BOC).sub.4
Thr(O.sup.tBu)-D-[(4-phenylphenyl)alanine]-6-PMB nonapeptide
[0933] To a solution of intermediate 18 (Cbz)(BOC).sub.4
Thr(O.sup.tBu)-D-[(4-Bromo)Phe]-6-PMB nonapeptide, 605 mg,
0.371mmol) was added benzene boronic acid (68 mg, 0.556 mmol),
palladium (II) acetate (8.3 mg, 0.0371 mmol), XPhos (35 mg, 0.0741
mmol) and potassium phosphate tribasic (157 mg, 0.741 mmol) in
toluene (10 mL) and the stirred mixture was degassed with nitrogen
for 2 minutes. The reaction was sealed and heated to 100.degree. C.
for 18 hours. After cooling the mixture was diluted with EtOAc and
water. The phases were separated and the aqueous layer was further
extracted with 10% IPA in EtOAc. The combined organics were dried
(MgSO.sub.4) and the solvent evaporated to afford a crude oil. This
was purified by chromatography: 40 g column, using a gradient of 0
to 10% MeOH in EtOAc to afford the desired compound as a colourless
glass m/z 1630 (MH.sup.+).
[0934] General Method 4: Hydrogenation with Platinum Oxide
[0935] Exemplified by the synthesis of
D-[Cyclohexyl]alanine-6-Polymyxin
##STR00024##
[0936] A suspension of platinum oxide (20 mg, 0.088 mmol) in acetic
acid (2 mL) was added to a stirred solution of polymyxin B (200 mg,
0.166 mmol) in acetic acid (20 mL). The reaction was hydrogenated
for 24 h at ambient temperature and atmospheric pressure. A further
200 mg Platinum oxide was added portionwise during the course of
the reaction. The reaction mixture was filtered through Celite and
washed with water (100 mL). The filtrate was evaporated at reduced
pressure to leave a beige solid. The solid was dissolved in water
(2 mL) and purified by preparative HPLC as described in the general
method 1. Product containing fractions were combined and
lyophilised to afford the title compound as the TFA salt m/z 1209.8
(MH.sup.+), C.sub.56H.sub.104N.sub.16O.sub.13 exact mass
1208.80.
[0937] General Method 5: Catalytic Transfer Hydrogenation with
Palladium on Carbon
[0938] Exemplified by the synthesis of
(Trans-5-(isobutyl-piperidine)-3-carbonyl L-Thr-L-Dap-polymyxin
D-[(4-octyl)Phe]-6-heptapeptide.
[0939] (Trans-5-(isobutyl -piperidine)-3-carbonyl
L-Thr-L-Dap-polymyxin D-[(4-(E)-oct-1-enyl)Phe]-6-heptapeptide
Isomer 1 was hydrogenated under the conditions described for
Intermediate 7 step 4 to afford the title compound. m/z
1228[MH.sup.+], 614[M+2H].sup.2+. C.sub.60H.sub.105N.sub.15O.sub.12
requires 1227.81.
Example 24
Polymyxin B[D-(4-cyano)Phe]-6
[0940] A suspension of (Boc).sub.5 D-[(4-Bromo)Phe]-6-polymyxin
(100 mg, 0.056 mmol), Zinc cyanide (45 mg, 0.383 mmol, 6.8 mol
equiv.) and 1,1'-bis(diphenylphosphino)ferrocene (6 mg, 2 mol
equiv.) in dry DMF (2 ml) was degassed and then treated with
tris(dibenzylideneacetone)dipalladium (0) (5 mg, 1 mol equiv). The
tube was sealed and heated to 100.degree. C. for 3 days. The
solvent was evaporated and the residue partitioned between water
and ethyl acetate. The organic phase was dried over anhydrous
magnesium sulfate and evaporated. The residue was chromatographed
on silica eluting with 0-10% (1% 0.880 ammonia in methanol) in
ethyl acetate, followed by further purification by preparative HPLC
eluting with 20-95% acetonitrile in water (plus 1% TFA).
Product-containing fractions were combined and evaporated to an
oil. This was dissolved in TFA (2 mL) and DCM (8 mL) and stirred at
room temperature for 6 h. The solvent was evaporated and the
residue lyophilized from water to afford the desired product as a
white solid (2.8 mg) , m/z 614[M+2H].sup.2+.
C.sub.57H.sub.97N.sub.17O.sub.13 requires 1227.75.
Example 29
L-Dab-L-Thr-L-Dap-polymyxin [D-(4-octyl Phe)]-6 heptapeptide
[0941] Step 1. (BOC).sub.3 D-[(4-Bromo)Phe]-6-Polymyxin
heptapeptide (Intermediate 16) was coupled to
(S)-2-((S)-2-Benzyloxycarbonylamino-3-tert-butoxy-butyrylamino)-3-tert-bu-
toxycarbonylamino-propionic acid according to the method for
Intermediate 7 step 3 to afford
CBZ-Tetra-(N-Boc)-L-Thr(O-.sup.tBu)-L-Dap-Polymyxin B
[D-(4-Bromo)Phe)]-6 heptapeptide.
[0942] Step 2. CBZ-Tetra-(N-Boc)-L-Thr(O-.sup.tBu)-L-Dap-Polymyxin
B [D-(4-Bromo)Phe)]-6 heptapeptide was treated with octenyl boronic
acid under the suzuki coupling conditions of General method 3, to
afford CBZ- Tetra-(N-Boc)-L-Thr(O-.sup.tBu)-L-Dap-Polymyxin B
[D-(4-oct-2-enyl)Phe)]-6 heptapeptide.
[0943] Step 3. CBZ-Tetra-(N-Boc)-L-Thr(O-.sup.tBu)-L-Dap-Polymyxin
B [D-(4-oct-2-enyl)Phe)]-6 heptapeptide was treated with ammonium
formate in the presence of 10% Palladium on Carbon, as described
for Intermediate 7, step 3 to afford
Tetra-(N-Boc)-L-Thr(O-.sup.tBu)-L-Dap-polymyxin B
[D-(4-octyl)Phe)]-6 heptapeptide.
[0944] Step 4 The product from Step 3 was coupled to
(S)-2-((2-(benzyloxy)-2-oxoethyl)amino)-4-((tert-butoxycarbonyl)amino)but-
anoic acid DCHA salt under the standard coupling conditions of
Intermediate 7 step 3, to afford tetra-(N-BOC)
L-Dab-L-Thr-L-Dap-polymyxin [D-(4-octyl Phe)]-6 heptapeptide.
[0945] Step 5. The product from Step 4 was deprotected as described
in the General method 1 step 2 , followed by preparative HPLC to
affords the title compound, L-Dab-L-Thr-L-Dap-polymyxin [D-(4-octyl
Phe)]-6 heptapeptide as a white solid m/z 1161[MH.sup.+],
581[M+2H].sup.2+. C.sub.54H.sub.96N.sub.16O.sub.12 requires
1160.74.
[0946] Synthesis of Carboxylic Acids
[0947] Carboxylic acids used for the assembly of polymyxin
derivatives were secured either via commercial sources, or prepared
using methods known to those skilled in the art. Experimental
details of the following carboxylic acids serve as representative
examples for the synthesis of similar acid intermediates used in
the synthesis of the compounds of the present invention.
[0948] 4-(tert-Butoxycarbonylamino)-2-(4-chlorophenyl)butanoic
acid
[0949] Step 1- Ethyl 2-(4-chlorophenyl)-2-oxo-acetate
##STR00025##
[0950] To a solution of diethyl oxalate (1 mL, 7.36 mmol) in
tetrahydofuran (10 mL) at -50.degree. C. was added
4-chlorophenylmagnesium bromide (1M solution in diethyl ether, 7.3
mL, 7.30 mmol). The reaction mixture was allowed to warm to
-15.degree. C. and stirred at that temperature for a further 1.5h.
The reaction was quenched by the addition of 1M hydrochloric acid
(7 mL) and stirred at room temperature for 2 minutes. The layers
were separated and then the aqueous phase was further extracted
with diethyl ether (.times.2). The combined organic phases were
dried over magnesium sulphate, filtered and concentrated at reduced
pressure to give the crude title compound as a yellow oil (1.63
g,>100%). m/z 235 (MNa.sup.+), C.sub.10H.sub.9ClO.sub.3 exact
mass 212.02.
[0951] Step 2- Ethyl-2-(4-chlorophenyl)-3-cyano-prop-2-enoate
##STR00026##
[0952] To a solution of crude ethyl
2-(4-chlorophenyl)-2-oxo-acetate (.about.7.3 mmol) in toluene (30
mL) was added (triphenylphosphoranylidene)acetonitrile (2.20 g,
7.30 mmol). The reaction mixture was stirred at room temperature
for 16 hours and then concentrated at reduced pressure. The product
was purified by silica gel chromatography eluting with 0-40% ethyl
acetate in iso-hexane to give the title compound as a colourless
oil (1.38 g, 81%). m/z 258 (MNa.sup.+), C.sub.12H.sub.10ClNO.sub.2
exact mass 235.04.
[0953] Step 3- Ethyl 4-amino-2-(4-chlorophenyl)butanoate
[0954] To a solution of
ethyl-2-(4-chlorophenyl)-3-cyano-prop-2-enoate (1.36 g, 5.79 mmol)
in methanol (60 mL) was added cobalt chloride (1.51 g, 11.6 mmol).
The reaction mixture was cooled to 0.degree. C. and then treated
with sodium borohydride (2.2 g, 57.8 mmol) portionwise. After the
addition, the reaction was stirred at 0.degree. C. for 1 hour. The
mixture was quenched by the addition of 1 M hydrochloric acid and
stirred at room temperature for 20 minutes. The pH was adjusted to
11 by the addition of 880 ammonia and then the mixture was filtered
through a pad of celite which was washed with dichloromethane.
After separation of the layers, the aqueous phase was re-extracted
with dichloromethane (.times.2). The combined organic layers were
dried over magnesium sulphate, filtered and concentrated to give
the title compound as a pale brown oil (838 mg, 60%). m/z 242
(MH.sup.+), C.sub.12H.sub.16ClNO.sub.2 exact mass 241.09.
[0955] Step 4- Ethyl 4-(tert-butoxycarbonylamino)-2-(4-ch
lorophenyl)butanoate
[0956] To a solution of ethyl 4-amino-2-(4-chlorophenyl)butanoate
(836 mg, 3.47 mmol) in dichloromethane (40 mL) was added
di-tert-butyl dicarbonate (1.06 g, 4.86 mmol). The reaction mixture
was stirred at room temperature for 16 hours and then concentrated
at reduced pressure. The product was purified by silica gel
chromatography eluting with 0-40% ethyl acetate in iso-hexane to
give the title compound as a colourless oil (784 mg, 66%). m/z 364
(MNa.sup.+), C.sub.17H.sub.24CINO.sub.4 exact mass 341.83.
[0957] Step
5-4-(tert-Butoxycarbonylamino)-2-(4-chlorophenyl)butanoic acid
##STR00027##
[0958] To a solution of ethyl
4-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)butanoate (780 mg,
2.29 mmol) in dioxane (10 mL) and water (10 mL) was added lithium
hydroxide monohydrate (300 mg, 7.14 mmol). The reaction mixture was
stirred at room temperature for 3 days and then concentrated at
reduced pressure. The residue was partitioned between diethyl ether
and water and the pH adjusted to 1 by the addition of 1 M
hydrochloric acid. After separation of the layers, the aqueous
phase was re-extracted with diethyl ether (.times.2). The combined
organic phases were dried over magnesium sulphate, filtered and
concentrated. The title compound was isolated as a colourless oil
(663 mg, 93%). m/z 312 (M-H).sup.-, C.sub.15H.sub.20ClNO.sub.4
exact mass 313.11.
[0959] (S)-2-(benzyloxy)-4-((tert-butoxycarbonyl)amino)butanoic
acid
[0960] Step 1- Methyl
(S)-2-(benzyloxy)-4-((tert-butoxycarbonyl)amino)butanoate
[0961] To a solution of methyl
(S)-4-((tert-butoxycarbonyl)amino)-2-hydroxybutanoate (see Dewitt
et al. Org. Biomol. Chem. 2011, 9, 1846) (233 mg, 1.0 mmol) in dry
ethyl acetate (10 mL) was added silver oxide (350 mg, 1.5 mmol)
followed by benzyl bromide (0.179 mL, 1.5 mmol). The mixture was
stirred in the dark at room temperature overnight, then heated to
50.degree. C. for 8 h. The mixture was cooled, filtered through
Kieselguhr, and evaporated. The residue was chromatographed on
silica eluting with 0-100% ethyl acetate in hexane to afford the
desired product as a colourless oil (67 mg, 20%). m/z 323.6.
C17H25NO5 requires 323.17
[0962] Step 2-
(S)-2-(benzyloxy)-4-((tert-butoxycarbonyl)amino)butanoic acid
##STR00028##
[0963] Methyl
(S)-2-(benzyloxy)-4-((tert-butoxycarbonyl)amino)butanoate (67 mg,
0.2 mmol) was dissolved in water (1 mL) and dioxane (2 mL). Lithium
hydroxide (15 mg) was added and the mixture stirred at room
temperature overnight. The resultant mixture was concentrated under
reduced pressure, diluted with water (4 mL) and washed with ethyl
acetate. The aqueous phase was adjusted to pH 2 with 1 M HCl and
extracted with dichloromethane (3.times.4 mL). The dichloromethane
extracts were combined and evaporated to give the title compounds
as a white solid (40 mg, 64%). m/z 309.6 (MH+), 332 (MNa+).
C16H23NO5 requires 309.16.
Additional Synthesis Examples
[0964] (S)-4-Amino-2-(cyclohexylmethoxy)butanoyl
L-Thr-L-Dap-polymyxin [D-cyclohexylalanine-6]-heptapeptide
(Compound 84)
[0965] (S)-4-Amino-2-(benzyloxy)butanoyl L-Thr-L-Dap-polymyxin
[D-cyclohexylalanine-6]-heptapeptide trifluoroacetate salt (Example
42) (18 mg) was dissolved in isopropanol (5 mL) and water (1 mL),
and treated with 5% rhodium on alumina (10 mg). The mixture was
stirred under an atmosphere of hydrogen for 18 h. The catalyst was
removed by filtration and the filtrate purified by preparative HPLC
using the conditions of General Method 3. Product-containing
fractions were combined, evaporated to low volume and lyophilized
to a while solid (0.8 mg). m/z 1153 [MH+], 1265 [M+TFA]+.
C.sub.53H.sub.97N.sub.15O.sub.13 requires 1151.74.
[0966] Changes to Amino Acid Residues at Positions 6 and/or 7
[0967] Example compounds 94 to 99 (as shown in Table 1C below) were
prepared by solid phase peptide synthesis, with the cyclisation
step carried out off-resin. Suitable methodology is given in WO
2014/188178 (Example 50). An alternative method of solid phase
synthesis is given in Velkov et aL and WO 2015/149131.
[0968] Structures depict the N-terminal group and side chain on the
Polymyxin heptapeptide scaffold (PMBH, shown below). Relative
stereochemistry is depicted by heavy or dashed lines. Absolute
stereochemistry is depicted by heavy or hashed wedged bonds.
##STR00029##
[0969] The compounds described below have an L-Thr residue at the
position corresponding to position 2 in polymyxin. The compounds
have either an L-Dap or an L-Dab residue at the position
corresponding to position 3 in polymyxin.
[0970] The present case is based on GB 1421020.7, the contents of
which are hereby incorporated by reference in their entirety. In
that case the stereochemistry of the Thr residue at position 2 of
some example compounds was incorrectly drawn. This is corrected in
the example compounds presented in the present case. In context it
is clear that the example compounds, including the compounds of the
invention, have an L-Thr residue at position 2 as the compounds are
prepared indirectly from polymyxin B, which retains L-Thr residue
at position 2, or the compounds are prepared from a polymyxin B
heptapeptide which is coupled with a L-Thr-containing group to
ultimately yield the appropriate N-terminal-derivatised nonapeptide
or decapeptide product.
[0971] It is noted also that the correct names for the example
compounds were used.
TABLE-US-00004 TABLE 1 R.sup.1 HPLC (N-terminal and side-chain on
Starting RT Ex heptapeptide R.sup.2 Formula Mass material Name
(min) m/z PMB ##STR00030## ##STR00031## C1 ##STR00032##
##STR00033## C52H89 N15O12 1115.7 Int 11 (trans-5-(isobutyl-
piperidine)-3-carbonyl L-Thr-L-Dap-polymyxin B heptapeptide 5.45
1117[MH+] 559[M + 2H].sup.2+ C2 ##STR00034## ##STR00035## C51H88
N16O12 1116.7 Int 11 (S)-1-isobutyl piperazine-2-carbonyl-
L-Thr-L-Dap-polymyxin B heptapeptide 5.12 1118[MH+] 559[M +
2H].sup.2+ C3 ##STR00036## ##STR00037## C62H10 2N16O1 3 1278.7
(BOC).sub.5 polymyxin [D-(4- bromo Phe)]-6] Polymyxin B[D-(4-
phenyl)Phe]-6] 6.67 1279.4[MH.sup.+] 640.3[M + 2H].sup.2+ 1
##STR00038## ##STR00039## C61H10 1N17O1 3 1279.77 6348 (BOC).sub.5
polymyxin [D-(4- bromo Phe)]-6 Polymyxin B[D-(4-(4-
pyridyl))Phe]-6] 5.64 1281[MH.sup.+] 641[M + 2H].sup.2+ 2
##STR00040## ##STR00041## C56H97 BrN16O 13 1280.66 0275 Polymyxin B
Polymyxin B[D-(4- bromoPhe)]-6] 6.48 1282[MH.sup.+] 642[M +
2H].sup.2+ 3 ##STR00042## ##STR00043## C58H93 N15O12 1191.71 2698
Int 16 (trans-5-(isobutyl- piperidine)-3-carbonyl
L-Thr-L-Dap-polymyxin [D-(4-phenyl)Phe]-6] heptapeptide. Isomer 1
6.19 1193[MH.sup.+] 597[M + 2H].sup.2+ 4 ##STR00044## ##STR00045##
C58H93 N15O12 1191.71 2698 Int 16 (trans-5-(isobutyl-
piperidine)-3-carbonyl L-Thr-L-Dap-polymyxin [D-(4-phenyl)Phe]-
6]heptapeptide. Isomer 2 6.40 1193[MH.sup.+] 597[M + 2H].sup.2+ 5
##STR00046## ##STR00047## C57H92 N16O12 1192.71 Int 16
(S)-1-isobutyl piperazine-2-carbonyl- L-Thr-L-Dap-polymyxin
[D-(4-phenyl)Phe]- 6]heptapeptide 6.14 1194[MH.sup.+] 597[M +
2H].sup.2+ 6 ##STR00048## ##STR00049## C62H10 2N16O1 2 1262.79 Int
16 (S)-1-octyl piperazine- 2-carbonyl-L-Thr-L- Dap-polymyxin [D-(4-
phenyl)Phe]- 6]heptapeptide 6.75 1265[MH.sup.+] 632[M + 2H].sup.2+
7 ##STR00050## ##STR00051## C62H10 1N15O1 2 1247.78 Int 16
trans-4-octylpyrrolidine- 3-carbonyl polymyxin [D-(4-phenyl)Phe]-6]
nonapeptide. Isomer 1 6.71 1248[MH.sup.+] 8 ##STR00052##
##STR00053## C62H10 1N15O1 2 1247.78 Int 16
trans-4-octylpyrrolidine- 3-carbonyl polymyxin [D-(4-phenyl)Phe]-6]
nonapeptide. Isomer 2 7.04 1248[MH.sup.+] 625[M + 2H].sup.2+ 9
##STR00054## ##STR00055## C62H10 1N15O1 2 1247.78 Int 17
trans-4-octylpyrrolidine- 3-carbonyl polymyxin [D-(2-phenyl)Phe]-6]
nonapeptide. Isomer 1 6.70 1249[MH.sup.+] 625[M + 2H].sup.2+ 10
##STR00056## ##STR00057## C62H10 1N15O1 2 1247.78 Int 17
trans-4-octylpyrrolidine- 3-carbonyl polymyxin [D-(2-phenyl)Phe]-6]
nonapeptide. Isomer 2 7.08 1249[MH.sup.+] 625[M + 2H].sup.2+ 11
##STR00058## ##STR00059## C52H88 BrN15O 12 1193.59 Int 16
(trans-5-(isobutyl- piperidine)-3-carbonyl L-Thr-L-Dap-polymyxin
[D-(4-bromo Phe)]-6] hept apeptide Isomer 1 5.91 1195/1197
[MH.sup.+] 598[M + 2H].sup.2+ 12 ##STR00060## ##STR00061## C52H88
BrN15O 12 1193.59 Int 16 (trans-5-(isobutyl- piperidine)-3-carbonyl
L-Thr-L-Dap-polymyxin [D-(4-bromo Phe)]-6] heptapeptide Isomer 2
6.12 1195/1197 [MH.sup.+] 598[M + 2H].sup.2+ 13 ##STR00062##
##STR00063## C49H84 BrN15O 12 1153.56 Int 16 2-aminomethyl-4-
methyl pentanoyl polymyxin L-Thr-L-Dap- polymyxin [D-(4-bromo
Phe)]-6]heptapeptide. Isomer 1 5.79 1155[MH.sup.+] 14 ##STR00064##
##STR00065## C49H84 BrN15O 12 1153.56 Int 16 2-aminomethyl-4-
methyl pentanoyl polymyxin L-Thr-L-Dap- polymyxin [D-(4-bromo
Phe)]-6]heptapeptide. Isomer 2 5.96 1155[MH.sup.+] 15 ##STR00066##
##STR00067## C55H89 N15O12 1151.68 Int 16 2-aminomethyl-4- mehtly
pentanoyl polymyxin L-Thr-L-Dap- polymyxin [D-(4-phenyl
Phe)]-6]heptapeptide. Isomer 1 6.21 1153[MH.sup.+] 16 ##STR00068##
##STR00069## C55H89 N15O12 1151.68 Int 16 2-aminomethyl-4- methyl
pentanoyl polymyxin L-Thr-L-Dap- polymyxin [D-(4-phenyl
Phe)]-6]heptapeptide. Isomer 2 6.36 1153[MH.sup.+] 17 ##STR00070##
##STR00071## C60H10 3N15O1 2 1225.79 Int 16 (trans-5-(isobutyl-
piperidine)-3-carbonyl L-Thr-L-Dap-polymyxin [D-(4-(E)-oct-1-enyl)
Phe]-6]heptapeptide Isomer 1 7.69 1226[MH.sup.+] 614[M + 2H].sup.2+
18 ##STR00072## ##STR00073## C60H10 3N15O1 2 1225.79 Int 16
(trans-5-(isobutyl- piperidine)-3-carbonyl L-Thr-L-Dap-polymyxin
[D-(4-(E)-oct-1-enyl)- Phe]-6]heptapeptide Isomer 2 7.84
1226[MH.sup.+] 614[M + 2H].sup.2+ 19 ##STR00074## ##STR00075##
C56H88 F2N15O 12 1219.67 Int 16 2-Aminomethyl-4- methyl pentanoyl
polymyxin L-Thr-L-Dap- polymyxin [D-{4-(4- trifluoromethyl) phenyl}
Phe]-6]heptapeptide. Isomer 1 6.84 1221[MH.sup.+] 20 ##STR00076##
##STR00077## C56H88 F3N15O 12 1219.67 Int 16 2-Aminomethyl-4-
methyl pentanoyl polymyxin L-Thr-L-Dap- polymyxin [D-{4-(4-
trifluoromethyl) phenyl} Phe]-6]heptapeptide. Isomer 1 6.95
1221[MH.sup.+] 21 ##STR00078## ##STR00079## C50H93 N15O12 1095.71
2- amino- meth- yl pentanoyl polymyxin B nonapeptide
2-Aminomethyl-4- methyl pentanoyl polymyxin D- [cyclohexyl
alanine]-6] nonapeptide. 5.84 1096.8[MH.sup.+] 22 ##STR00080##
##STR00081## C56H10 4N16O1 3 1208.80 Polymyxin B Polymyxin [D-
cyclohexyl alanine]-6] 6.54 1209.8[MH.sup.+] 23 ##STR00082##
##STR00083## C.sub.60H.sub.105 N.sub.15O.sub.12 1227.81 Example 18
(Trans-5-(isobutyl- piperidine)-3-carbonyl L-Thr-L-Dap-polymyxin
[D-(4-octyl Phe)]-6 heptapeptide 7.99 1228[MH.sup.+] 614[M +
2H].sup.2+ 24 ##STR00084## ##STR00085## C57H97 N17O13 1227.75
(Boc).sub.5 [D- (4- Bromo) Phe-6]- Polymyxin Polymyxin B[D-(4-
cyano)Phe]-6 6.19 1229[MH.sup.+] 614[M + 2H].sup.2+ 25 ##STR00086##
##STR00087## C56H97 N15O12 1171.74 Int 16 (Ttrans-5-(isobutyl-
piperidine)-3-carbonyl L-Thr-L-Dap-polymyxin [D-(4-isobutyl Phe)]-
6]heptapeptide isomer 2 6.76 1173[MH.sup.+] 587[M + 2H].sup.2+ 26
##STR00088## ##STR00089## C61H10 1N15O1 2C61H1 01N15O 12 1235.78
Int 16 2-(2- Aminoethyl)undecanoyl L-Thr-L-Dap-polymyxin
[D-{4-(4-trifluoromethyl) phenyl}Phe]-6 heptapeptide. Isomer 2 7.38
1237[MH.sup.+] 619[M + 2H].sup.2+
TABLE-US-00005 TABLE 1A Additional Synthesis Examples HPLC R.sup.1
Starting RT Ex (N-terminal and side-chain on heptapeptide R.sup.2
Formula Mass material Name (min) m/z C4 ##STR00090## ##STR00091##
C51H89 N15O12 1103.68 Int 7 2-(2- Aminoethyl) hexanoyl polymyxin B
nonapeptide 5.31 1104.7 [MH.sup.+] C5 ##STR00092## ##STR00093##
C53H93 N15O12 1131.71 Int 7 2-(2- Aminoethyl) octanoyl polymyxin B
nonapeptide 5.91 1132.7 [MH.sup.+] 567 [M + 2H].sup.2+ C6
##STR00094## ##STR00095## C52H91 N15O12 1117.70 Int 11 2-(2-
Aminoethyl) octanoyl L- Thr-L-Dap- polymyxin heptapeptide 5.97
1161.2 [MH.sup.+] 27 ##STR00096## ##STR00097## C55H95 N15O12
1157.73 Int 16 2-(Aminomethyl)- 4- methylpentanoyl L-Thr-L-Dap-
polymyxin [D-(4- cyclohexyl Phe)]- 6 heptapeptide 6.85 1159
[MH.sup.+] 580 [M + 2H].sup.2+ 28 ##STR00098## ##STR00099## C51H93
N15O12 1107.71 Int 19 3-Amino-2- cyclohexylpropanoyl L-Thr-L-Dap-
polymyxin [D- cyclohexylalanine]- 6 heptapeptide 6.05 1108.8
[MH.sup.+] 29 ##STR00100## ##STR00101## C54H96 N16O12 1160.74 Int
16 L-Dab-L-Thr-L- Dap-polymyxin [D-(4-octyl Phe)]- 6 heptapeptide
7.50 1161 [MH.sup.+] 581 [M + 2H].sup.2+ 30 ##STR00102##
##STR00103## C61H100 N16O12 1248.77 Int 16 (S)-1- Octylpiperazine-
2-carbonyl L-Thr- L-Dap-polymyxin [D-(4-phenyl Phe)]-6
heptapeptide. 6.73 1249.8 [MH.sup.+] 31 ##STR00104## ##STR00105##
C52H95 N15O12 1121.73 Int 19 3-amino-2- (cyclohexylmethyl)
propanoyl L- Thr-L-Dap- polymyxin [D- cyclohexylalanine]- 6
heptapeptide 6.08 1122.7 [MH.sup.+] 32 ##STR00106## ##STR00107##
C51H93 N15O12 1107.71 Int 19 3-amino-3- cyclohexylpropanoyl
L-Thr-L-Dap- polymyxin [D- cyclohexylalanine]- 6 heptapeptide.
Isomer 1 5.84 1108.8 [MH.sup.+] 33 ##STR00108## ##STR00109## C51H93
N15O12 1107.71 Int 19 3-amino-3- cyclohexylpropanoyl L-Thr-L-Dap-
polymyxin [D- cyclohexylalanine]- 6 heptapeptide. Isomer 2 5.93
1108.7 [MH.sup.+] 34 ##STR00110## ##STR00111## C52H89 N15O12
1115.68 Int 19 3-amino-2- benzylpropanoyl L-Thr-L-Dap- polymyxin
[D- cyclohexylalanine]- 6 heptapeptide. Isomer 2 5.95 1119
[MH.sup.+] 559 [M + 2H].sup.2+ 35 ##STR00112## ##STR00113## C53H91
N15O12 1129.70 Int 19 4-amino-2- benzylbutanoyl L-Thr-L-Dap-
polymyxin [D- cyclohexylalanine]- 6 heptapeptide. Isomer 2 5.98
1131 [MH.sup.+] 566 [M + 2H].sup.2+ 36 ##STR00114## ##STR00115##
C54H93 N15O12 1143.71 Int 20 4-amino-2- benzylbutanoyl- polymyxin
[D- cyclohexylalanine]- 6 nonapeptide. isomer 2 5.97 1144
[MH.sup.+] 573 [M + 2H].sup.2+ 37 ##STR00116## ##STR00117## C55H100
N16O14 1208.76 Int 20 2-cyclohexyl-2- hydroxyacetyl polymyxin [D-
cyclohexylalanine]- 6 nonapeptide 5.75 1209.6 [MH+] 606 [M +
2H].sup.2+ 38 ##STR00118## ##STR00119## C52H89 N15O12 1115.68 Int
19 4-amino-2- phenylbutanoyl L-Thr-L-Dap- polymyxin [D-
cyclohexylalanine]- 6 heptapeptide. isomer 2 5.72 1116.7 [MH.sup.+]
39 ##STR00120## ##STR00121## C52H89 N15O12 1115.68 Int 19
4-amino-3- phenylbutanoyl L-Thr-L-Dap- polymyxin [D-
cyclohexylalanine]- 6 heptapeptide. 5.70 1116.7 [MH.sup.+] 40
##STR00122## ##STR00123## C51H95 N15O12 1109.73 Int 20 2-(2-
aminoethyl) hexanoyl [D- cyclohexylalanine]- 6 nonapeptide. 5.76
1111 [MH.sup.+] 556 [M + 2H].sup.2+ 41 ##STR00124## ##STR00125##
C50H93 N15O12 1095.71 Int 19 2-(2- aminoethyl) hexanoyl L-Thr-L-
Dap-polymyxin [D- cyclohexylalanine]- 6 heptapeptide. Isomer 2 5.84
1097 [MH.sup.+] 549 [M + 2H].sup.2+ 42 ##STR00126## ##STR00127##
C52H95 N15O12 1121.73 Int 19 4-amino-3- cyclohexylbutanoyl
L-Thr-L-Dap- polymyxin [D- cyclohexylalanine]- 6 heptapeptide.
Isomer 1 5.88 1122.7 [MH.sup.+] 43 ##STR00128## ##STR00129## C52H95
N15O12 1121.73 Int 19 4-amino-3- cyclohexylbutanoyl L-Thr-L-Dap-
polymyxin [D- cyclohexylalanine]- 6 heptapeptide. isomer 2 5.95
1122.7 [MH.sup.+] 44 ##STR00130## ##STR00131## C52H88 FN15O12
1133.67 Int 19 4-amino-2-(4- fluorophenyl) butanoyl L-Thr-L-
Dap-polymyxin [D- cyclohexylalanine]- 6 heptapeptide. Isomer 2 5.75
1135 [MH.sup.+] 568 [M + 2H].sup.2+ 45 ##STR00132## ##STR00133##
C53H90 FN15O12 1147.69 Int 19 4-amino-2-(3- fluorobenzyl) butanoyl
L-Thr-L- Dap-polymyxin [D- cyclohexylalanine]- 6 heptapeptide.
isomer 2 5.90 1149 [MH.sup.+] 575 [M + 2H].sup.2+ 46 ##STR00134##
##STR00135## C50H93 N15O13 1111.71 Int 19 (S)-4-amino-2-
butoxybutanoyl L-Thr-L-Dap- polymyxin [D- cyclohexylalanine]- 6
heptapeptide. 5.64 1113 [MH.sup.+] 557 [M + 2H].sup.2+ 47
##STR00136## ##STR00137## C51H95 N15O12 1109.73 Int 19
2-(2-aminoethyl)- 4-methylhexanoyl L-Thr-L-Dap- polymyxin [D-
cyclohexylalanine]- 6 heptapeptide. Isomer 2 5.91 1111 [MH.sup.+]
556 [M + 2H].sup.2+ 48 ##STR00138## ##STR00139## C53H91 N15O13
1145.69 Int 19 (S)-4-amino-2- (benzyloxy) butanoyl L-Thr-L-Dap-
polymyxin [D- cyclohexylalanine]- 6 heptapeptide. 5.72 1146.7
[MH.sup.+] 1259 [M + TFA] 49 ##STR00140## ##STR00141## C52H98
N16O12 1138.76 Int 19 (S)-4-amino-2- (hexylamino) butanoyl L-Thr-L-
Dap-polymyxin [D- cyclohexylalanine]- 6 heptapeptide. 5.89 1139.6
[MH.sup.+] 50 ##STR00142## ##STR00143## C52H88 ClN15O12 1149.64 Int
19 4-amino-3-(4- chlorophenyl) butanoyl L-Thr-L- Dap-polymyxin [D-
cyclohexylalanine]- 6 heptapeptide. Isomer 1 5.61 1150.5 [MH.sup.+]
51 ##STR00144## ##STR00145## C52H88 ClN15O12 1149.64 Int 19
4-amino-3-(4- chlorophenyl) butanoyl L-Thr-L- Dap-polymyxin [D-
cyclohexylalanine]- 6 heptapeptide. Isomer 2 5.66 1150.4 [MH.sup.+]
52 ##STR00146## ##STR00147## C52H96 N16O12 1136.74 Int 20 (S)-1-
isobutylpiperazine- 2-carbonyl polymyxin [D- cyclohexylalanine]- 6
nonapeptide 5.50 1137 [MH.sup.+] 570 [M + 2H].sup.2+ 53
##STR00148## ##STR00149## C53H91 N15O12 1129.70 Int 20 3-amino-2-
benzylpropanoyl polymyxin [D- cyclohexylalanine]- 6 nonapeptide.
Isomer 2 5.87 1131 [MH.sup.+] 566 [M + 2H].sup.2+ 54 ##STR00150##
##STR00151## C53H90 FN15O12 1147.69 Int 20 4-amino-2-(4-
fluorophenyl) butanoyl polymyxin [D- cyclohexylalanine]- 6
nonapeptide isomer 2 5.84 1149 [MH.sup.+] 575 [M + 2H].sup.2+ 55
##STR00152## ##STR00153## C53H90 ClN15O12 1163.66 Int 20
4-amino-2-(3- chlorophenyl) butanoyl polymyxin [D-
cyclohexylalanine]- 6 nonapeptide. isomer 2 5.95 1164 [MH.sup.+] 56
##STR00154## ##STR00155## C53H91 N15O12 1129.70 Int 20 4-amino-3-
phenylbutanoyl polymyxin [D- cyclohexylalanine]- 6 nonapeptide
isomer 1 5.57 1130.5 [MH.sup.+] 57 ##STR00156## ##STR00157## C53H91
N15O12 1129.70 Int 20 4-amino-3- phenylbutanoyl polymyxin [D-
cyclohexylalanine]- 6 nonapeptide isomer 2 5.60 1130.5 [MH.sup.+]
58 ##STR00158## ##STR00159## C53H91 N15O12 1129.70 Int 19
4-amino-3- benzylbutanoyl L-Thr-L-Dap- polymyxin [D-
cyclohexylalanine]- 6 heptapeptide. Isomer 1 5.83 1131 [MH.sup.+]
566 [M + 2H].sup.2+ 59 ##STR00160## ##STR00161## C53H91 N15O12
1129.70 Int 19 4-amino-3- benzylbutanoyl L-Thr-L-Dap- polymyxin [D-
cyclohexylalanine]- 6 heptapeptide. Isomer 2 5.90 1131 [MH.sup.+]
566 [M + 2H].sup.2+ 60 ##STR00162## ##STR00163## C52H89 N15O12
1115.68 Int 19 4-amino-4- phenylbutanoyl L-Thr-L-Dap- polymyxin [D-
cyclohexylalanine]- 6 heptapeptide. Isomer 1 5.67 1118 [MH.sup.+]
559 [M + 2H].sup.2+ 61 ##STR00164## ##STR00165## C52H89 N15O12
1115.68 Int 19 4-amino-4- phenylbutanoyl L-Thr-L-Dap- polymyxin [D-
cyclohexylalanine]- 6 heptapeptide. Isomer 2 5.69 1117 [MH.sup.+]
559 [M + 2H].sup.2+ 62 ##STR00166## ##STR00167## C53H90 FN15O12
1147.69 Int 20 3-amino-2-(2- fluorobenzyl) propanoyl 5.85 1150
[MH.sup.+] 575 [M + 2H].sup.2+ 63 ##STR00168## ##STR00169## C52H95
N15O12 1121.73 Int 19 4-amino-4- cyclohexylbutanoyl L-Thr-L-Dap-
polymyxin [D- cyclohexylalanine]- 6 heptapeptide. 5.81 1123
[MH.sup.+] 562 [M + 2H].sup.2+ 64 ##STR00170## ##STR00171## C53H91
N15O12 1129.70 Int 20 4-amino-2- phenylbutanoyl polymyxin [D-
cyclohexylalanine]- 6 nonapeptide isomer 2 5.72 1130.5 [MH.sup.+]
65 ##STR00172## ##STR00173## C53H90 FN15O12 1147.69 Int 19
4-amino-2-(2- fluorobenzyl) butanoyl L-Thr-L- Dap-polymyxin [D-
cyclohexylalanine]- 6 heptapeptide. Isomer 2 5.90 1149 [MH.sup.+]
66 ##STR00174## ##STR00175## C54H93 N15O12 1143.71 Int 20
4-amino-3- benzylbutanoyl polymyxin [D- cyclohexylalanine]- 6
nonapeptide isomer 1 5.71 1146 [MH.sup.+] 573 [M + 2H].sup.2+ 67
##STR00176## ##STR00177## C54H93 N15O12 1143.71 Int 20 4-amino-3-
benzylbutanoyl polymyxin [D- cyclohexylalanine]- 6 nonapeptide
isomer 2 5.79 1145 [MH.sup.+] 573 [M + 2H].sup.2+ 68 ##STR00178##
##STR00179## C51H89 N15O12S 1135.65 Int 19 4-amino-2- (thiophen-3-
ylmethyl)butanoyl L-Thr-L-Dap- polymyxin [D- cyclohexylalanine]- 6
heptapeptide. 5.77 1138 [MH.sup.+] 570 [M + 2H].sup.2+ 69
##STR00180## ##STR00181## C53H97 N15O12 1135.74 Int 20 4-amino-2-
cyclohexylbutanoyl polymyxin [D- cyclohexylalanine]- 6 nonapeptide
isomer 2 7.86 1136.6 [MH.sup.+] 70 ##STR00182## ##STR00183## C51H89
N15O12S 1135.65 Int 20 4-amino-2- (thiophen-2- yl)butanoyl
polymyxin [D- cyclohexylalanine]- 6 nonapeptide isomer 2 5.71 1137
[MH.sup.+] 569 [M + 2H].sup.2+ 71 ##STR00184## ##STR00185## C54H93
N15O13 1159.71 Int 19 (S)-4-amino-2- ((4- methylbenzyl)oxy)
butanoyl L-Thr- L-Dap-polymyxin [D- cyclohexylalanine]- 6
heptapeptide. 5.95 1160.6 [MH.sup.+] 1273 [M + TFA].sup.+ 72
##STR00186## ##STR00187## C54H99 N15O12 1149.76 Int 20 4-amino-3-
(cyclohexylmethyl) butanoyl polymyxin [D- cyclohexylalanine]- 6
nonapeptide 6.27 1150.5 [MH.sup.+] 73 ##STR00188## ##STR00189##
C53H97 N15O12 1135.74 Int 20 (trans-5-(isobutyl- piperidine)-3-
carbonyl polymyxin [D- cyclohexylalanine]- 6 nonapeptide 6.15
1136.6 [MH.sup.+] 74 ##STR00190## ##STR00191## C53H90 ClN15O13
1179.65 Int 19 (S)-4-amino-2-((4- chlorobenzyl)oxy) butanoyl L-Thr-
L-Dap-polymyxin [D- cyclohexylalanine]-6 heptapeptide. 6.16 1180.5
[MH.sup.+] 1293.5 [M + TFA].sup.+ 75 ##STR00192## ##STR00193##
C52H95 N15O12 1121.73 Int 19 4-amino-2- (cyclopentylmethyl)
butanoyl L- Thr-L-Dap- polymyxin [D- cyclohexylalanine]- 6
heptapeptide. 6.15 1123 [MH.sup.+] 562 [M + 2H].sup.2+ 76
##STR00194## ##STR00195## C52H88 ClN15O12 1149.64 Int 19
4-amino-2-(2- chlorophenyl) butanoyl L-Thr-L- Dap-polymyxin [D-
cyclohexylalanine]- 6 heptapeptide. 6.01 1151 [MH.sup.+] 77
##STR00196## ##STR00197## C53H90 ClN15O12 1163.66 Int 20
4-amino-2-(2- chlorophenyl) butanoyl polymyxin [D-
cyclohexylalanine]- 6 nonapeptide 5.97 1166 [MH.sup.+] 583 [M +
2H].sup.2+ 78 ##STR00198## ##STR00199## C53H91 N15O13 1145.69 Int
19 (S)-3-amino-2-((4- methylbenzyl)oxy) propanoyl L-Thr-
L-Dap-polymyxin [D- cyclohexylalanine]- 6 heptapeptide 6.09 1146.7
[MH.sup.+] 79 ##STR00200## ##STR00201## C52H88 ClN15O12 1149.64 Int
19 4-Amino-2-(3- chlorophenyl) butanoyl L-Thr-L- Dap-polymyxin [D-
cyclohexylalanine]- 6 heptapeptide. 5.89 1151 [MH.sup.+] 576 [M +
2H].sup.2+
TABLE-US-00006 TABLE 1B Further Additional Synthesis Examples HPLC
R.sup.1 Starting RT Ex (N-terminal and side-chain on heptapeptide
R.sup.2 Formula Mass material Name (min) m/z 80 ##STR00202##
##STR00203## C51H95 N15O12 1109.73 Int 19 2-(2-aminoethyl)- 5-
methylhexanoyl L-Thr-L-Dap- polymyxin [D- cyclohexylalanine-
6]heptapeptide. isomer 2 5.93 1111 [MH.sup.+] 81 ##STR00204##
##STR00205## C52H88 ClN15O13 1165.64 Int 19 (S)-3-amino-2- ((4-
chlorobenzyl)oxy) propanoyl L-Thr- L-Dap-polymyxin [D-
cyclohexylalanine- 5.97 1167 [MH.sup.+] 6]heptapeptide 82
##STR00206## ##STR00207## C53H90 ClN15O13 1179.65 Int 19
4-amino-2-((3- chlorobenzyl)oxy) butanoyl L-Thr- L-Dap-polymyxin
[D- cyclohexylalanine- 6]heptapeptide. Isomer 1 5.93 1180
[MH.sup.+] 83 ##STR00208## ##STR00209## C53H97 N15O12 1135.74 Int
20 4-amino-2- (cyclopentylmethyl) butanoyl polymyxin [D-
cyclohexylalanine- 6]nonapeptide 6.10 1137 [MH.sup.+] 84
##STR00210## ##STR00211## C53H97 N15O13 1151.74 Example 48
(S)-4-amino-2- (cyclohexyl- methoxy) butanoyl L- Thr-L-Dap-
polymyxin [D- cyclohexylalanine- 6]heptapeptide. 6.12 1153
[MH.sup.+], 1265 [M + TFA].sup.+ 85 ##STR00212## ##STR00213##
C52H95 N15O12 1121.73 Int 19 4-amino-2- cyclohexylbutanoyl
L-Thr-L-Dap- polymyxin [D- cyclohexylalanine- 6]heptapeptide. 6.09
1123 [MH.sup.+] 86 ##STR00214## ##STR00215## C53H97 N15O12 1135.74
Example 56 4-amino-3- cyclohexylbutanoyl polymyxin [D-
cyclohexylalanine- 6]nonapeptide. Isomer 1 5.95 1137 [MH.sup.+] 87
##STR00216## ##STR00217## C53H97 N15O12 1135.74 Example 57
4-amino-3- cyclohexylbutanoyl polymyxin [D- cyclohexylalanine-
6]nonapeptide. Isomer 2 6.04 1137 [MH.sup.+] 88 ##STR00218##
##STR00219## C56H97 N15O13 1187.74 Int 19 (S)-4-amino-2-((4-
isopropylbenzyl) oxy)butanoyl L- Thr-L-Dap- polymyxin [D-
cyclohexylalanine- 6]heptapeptide 6.44 1189 [MH.sup.+] 89
##STR00220## ##STR00221## C52H97 N15O12 1123.74 Int 20
2-(2-aminoethyl)- 5-methylhexanoyl polymyxin [D- cyclohexylalanine-
6]nonapeptide. Isomer 2 5.21 1125 [MH.sup.+] 90 ##STR00222##
##STR00223## C55H95 N15O13 1173.72 Int 19 (S)-4-amino-2- ((3,5-
dimethylbenzyl) oxy)butanoyl L- Thr-L-Dap- polymyxin [D-
cyclohexylalanine- 6]heptapeptide 5.63 1175 [MH.sup.+] 91
##STR00224## ##STR00225## C54H99 N15O12 1149.76 Example 66
4-amino-3- (cyclohexylmethyl) butanoyl polymyxin [D-
cyclohexylalanine- 6]nonapeptide. Isomer 1 6.05 1151 [MH.sup.+] 92
##STR00226## ##STR00227## C53H99 N15O12 1137.76 Int 20
2-(2-aminoethyl)- 4-ethylhexanoyl polymyxin [D- cyclohexylalanine]-
6 nonapeptide. Isomer 2 5.79 1139 [MH.sup.+] 93 ##STR00228##
##STR00229## C53H97 N15O12 1135.74 Tri-(N- Boc) Polymyxin B
heptapeptide 4-amino-2- cyclohexylbutanoyl polymyxin L-
alloThr-L-Dap- [D- cyclohexylalanine- 6]-heptapeptide.
[0972] Additional compounds with modifications at position 6 and/or
7, in general structure A, are shown in Table 1C:
##STR00230##
TABLE-US-00007 TABLE 1C Further Additional Synthesis Examples
R.sup.1 Ex (N-terminal and side-chain on heptapeptide R.sup.2
R.sup.3 Formula Mass Name 94 ##STR00231## ##STR00232## ##STR00233##
C52H89 N15O12 1115.7 4-amino-2- cyclohexylbutanoyl L-Thr-L-Dap-
polymyxin[norleu- 7] heptapeptide. 95 ##STR00234## ##STR00235##
##STR00236## C55H87 N15O12 1149.7 4-amino-2- cyclohexylbutanoyl
L-Thr-L-Dap- polymyxin[Phe-7] heptapeptide 96 ##STR00237##
##STR00238## ##STR00239## C54H91 N15O12 1141.7 4-amino-2-
cyclohexylbutanoyl L-Thr-L-Dap- polymyxin[L- cyclohexylglycine- 7]
heptapeptide 97 ##STR00240## ##STR00241## ##STR00242## C53H97
N15O12 1135.7 4-amino-2- cyclohexylbutanoyl polymyxin E [L-
cyclohexylalanine- 7] nonapeptide 98 ##STR00243## ##STR00244##
##STR00245## C52H95 N15O12 1121.7 4-amino-2- cyclohexylbutanoyl
polymyxin[D- cyclohexylglycine- 6] nonapeptide 99 ##STR00246##
##STR00247## ##STR00248## C52H95 N15O12 1121.7 4-amino-2-
cyclohexylbutanoyl L-Thr-L-Dab- polymyxin [D- cyclohexylalanine-
6], [norVal-7] heptapeptide
BIOLOGICAL ACTIVITY
[0973] To evaluate the potency and spectrum of the compounds,
susceptibility testing was performed against up to nine strains of
each of the Gram negative pathogens, Escherichia coli, Pseudomonas
aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii.
[0974] Comparator compounds C1 to C3 were also tested along with
Polymyxin B.
[0975] Biological data is presented for examples and comparator
compounds.
[0976] The values in Table 2 are MIC (.mu.g/mL) against strains of
E. Coll, K. pneumoniae, P. aeruginosa and A. baumanii, including
strains which show elevated MICs to Polymyxin.
[0977] The data shows that the introduction of a halogen atom to
D-phenylalanine at position 6 enhances activity against polymyxin
resistant strains (see Example 2 compared with PMB).
[0978] The introduction of a lipophilic substituent to the phenyl
group of the D-phenylalanine at position 6 significantly improves
of activity against resistant strains (see Example 4 and C1, and
Example 5 and C2).
[0979] The modification of the N terminal group further improves
the activity of the compounds against resistant strains (see
Example 4 and Example 5 compared to C3).
[0980] The authors have demonstrated a significant difference in
activity between diastereomers in some examples where a compounds
has been prepared in two diastereomeric forms in the N-terminal
group.
[0981] Additional compounds were prepared and the additional
biological data is presented in
[0982] Table 2A. The additional compounds were compared against PMB
and comparator compounds C4-C7. Comparator compounds C4-C6 are
shown in Table 1A. Comparator compound C7 corresponds to
octanoyl-Dab-Thr-Dab-Cy[Dab-Dab-D-Phe-L-OctGly-Dab-Dab-Thr]
reported as FADDI-002 by Velkov et al. (ACS Chemical Biology, 2014,
9, 1172).
[0983] The values in Table 2A are MIC (.mu.g/mL).
[0984] Further the inventors have found that in order to provide a
polymyxin derivative with a desirable combination of properties
(activity against polymyxin-susceptible strains, activity against
strains with reduced susceptibility to polymyxins i.e. MIC.ltoreq.4
.mu.g/mL, cytotoxicity, pharmacokinetics, tissue distribution) it
may be helpful to modify both the polymyxin N-terminal group and
the amino acid residues at position 6 and/or position 7.
[0985] For a given N-terminal group, increasing the lipophilicity
of the side-chains of the amino acid residues at position 6 and/or
position 7 improves the activity of a compound against strains with
reduced susceptibility to polymyxins (MIC.ltoreq.4 .mu.g/mL;
so-called `polymyxin-resistant strains`) as has been discussed
above.
[0986] The substituents to the core of the molecule and at the
N-terminus should not be considered in isolation and the present
inventors have found that the combination of these groups both
based on their specific geometries as well as the overall
lipophilicity of the molecule is very important for the optimum
biological properties.
[0987] The lipophilicity of a compound can be expressed as the logP
where P is the octanol:water partition coefficient. Methods of
estimation of this parameter are well known, and one such method of
estimation uses the calculated value A log P. The A Log P is a
calculation of the Ghose/Crippen group-contribution estimate for
Log P, where P is the relative solubility of a compound in octanol
versus water (Ghose, A. K., Viswanadhan, V. N., and Wendoloski, "J.
J., Prediction of Hydrophobic (Lipophilic) Properties of Small
Organic Molecules Using Fragment Methods: An Analysis of A log P
and C Log P Methods." J. Phys. Chem. A, 1998, 102, 3762-3772).
[0988] Velkov et al. have shown that providing highly lipophilic
moieties as the side-chains of the amino acid residues at position
6 and/or position 7 in polymyxin decapeptides (with either the
natural polymyxin acyl chain or a suitable replacement acyl group
at the N-terminus of a decapeptide) improves activity against
resistant strains (see Velkov et al. ACS Chem Biol 9, 1172;
2014).
[0989] The present inventors have found that the activity of such
compounds can be further improved using the N-terminal groups
described herein. For example, compound 26 shows further improved
activity against polymyxin-resistant strains compared with C7,
which is compound FADDI-02 reported by Velkov et al. The biological
activity of compound 26 compared with C7 is reported in Table 2C.
The values in Table 2C are MIC (.mu.g/mL).
[0990] Thus derivatised polymyxin compounds can be provided with an
optimum activity against polymyxin-resistant strains where the
combination of N-terminal moieties and amino acid residues at
position 6 and position 7 is chosen to give an overall AlogP value
greater (i.e. less negative) than -4.0, ideally greater than -3.5,
such as between -3.0 and -2.0.
[0991] It can be seen that compounds such as 26 and C7 are less
active against polymyxin-susceptible strains than compounds in a
more negative A Log P range. The present inventors have found that
compounds having a A Log P values lying in the range -5.0 to -6.3,
such as within the range -5.5 and -6.3, provided they have
N-terminal groups with optimum geometry, can have excellent
activity against both polymyxin-susceptible and resistant
strains.
[0992] Compounds with A Log P in this region with appropriate
N-terminal moieties and amino acid moieties at position 6 and
positon 7 can also have reduced cytotoxicity compared with
polymyxin B.
[0993] If certain favourable moieties are present at the N terminal
of the polymyxin scaffold then the A Log P value may not fall into
the optimum range. Modulating lipophilicity by changing the side
chains of amino acids 6 and/or 7 may bring such compounds into the
optimum range.
[0994] For example, Comparator compound C4 (A Log P 6.5) with a
short alkyl side chain has only moderate activity. This can be
improved by increasing the lipophilicity either at the N-terminus
with C5 (A Log P 5.5), or by increasing the lipophilicity of the
side chain of amino acid 6 by reduction to a cyclohexyl (see
compound 40; A Log P 5.8). In some instances increasing
lipophilicity in the core (at the amino acid positions 6 and/or 7)
rather than the N-terminal moiety can lead to improved biological
properties e.g. compound 41 has significantly lower cytotoxicity
compared with C6.
TABLE-US-00008 TABLE 2 E. coli K. pneumoniae P. aeruginosa A.
baumanii ATCC ATCC ATCC ATCC Ex. 058 059 060 061 25922 062 063 064
065 066 067 4352 068 070 27853 053 056 BAA-747 PMB 4 4 4 16 0.25
128 32 8 4 8 128 0.25 8 32 0.5 128 32 0.25 C1 1 2 1 2 0.03 32 8 2 2
1 64 0.03 2 4 0.25 16 1 0.06 C2 8 16 8 32 0.25 ND 128 32 16 32
>256 0.125 32 ND 0.5 >256 256 0.25 C3 2 1 4 8 0.5 32 8 4 0.5
4 32 0.5 2 4 1 16 16 1 1 ND ND 8 32 1 >64 >64 32 ND 32 >32
1 32 >32 1 >32 >32 1 2 2 1 2 4 2 8 16 2 0.5 4 16 1 2 4 1
16 4 2 3 8 8 16 32 0.5 >64 >64 32 32 ND >64 0.5 4 4 1 64 4
2 4 0.5 0.5 0.5 2 0.5 ND 4 2 1 1 8 0.5 1 2 1 2 0.5 0.5 5 1 1 2 8
0.06 ND 16 4 0.5 8 32 0.25 4 8 0.5 32 4 0.125 6 1 0.5 1 2 1 4 4 2 1
0.5 4 1 2 2 ND 8 4 1 7 2 1 4 8 1 16 32 8 1 4 32 1 2 2 ND 8 4 1 8 2
1 2 4 1 4 ND 1 1 0.5 8 1 2 2 1 4 2 1 9 2 2 4 8 1 64 >64 64 8 32
>64 0.5 2 2 1 64 32 1 10 1 1 2 2 2 2 8 2 1 4 4 1 2 2 2 4 4 1 11
16 32 16 64 1 >64 >64 >64 64 >64 >64 1 8 16 1 >64
32 2 12 0.25 1 1 1 0.125 8 4 1 0.5 1 8 0.125 1 1 0.25 8 ND 0.125 13
32 32 32 >64 1 >64 >64 >64 >64 >64 >64 0.5 32
64 0.5 >64 >64 >8 14 4 8 8 16 0.25 8 64 8 8 8 >64 0.25
8 16 0.5 32 16 0.125 15 32 16 32 64 1 >64 >64 >64 64 64
>64 0.5 16 32 1 >64 >64 8 16 4 1 5 16 0.25 4 16 2 1 4 32
0.5 4 8 0.5 16 4 0.25 17 2 2 2 2 2 4 16 8 4 ND 32 2 4 4 2 2 2 2 18
2 1 2 2 2 2 4 4 2 2 4 2 4 4 2 2 2 2 19 16 ND ND ND 1 ND ND ND 16 ND
ND 1 ND ND 2 ND ND 1 20 4 ND ND ND 1 ND ND ND 1 ND ND 0.5 ND ND 1
ND ND 0.5 21 8 16 8 32 0.25 16 64 8 ND 16 >64 0.25 32 32 0.5
>64 64 0.5 22 2 2 4 8 0.5 16 32 4 1 4 64 0.5 4 4 1 64 32 0.5 23
2 2 2 2 2 4 8 4 2 2 4 1 4 4 2 2 1 2
TABLE-US-00009 TABLE 2A Additional Microbial Activity E. coli K.
pneumoniae P. aeruginosa A. baumanii ATCC NCTC ATCC ATCC CCUG ATCC
NCTC ATCC Ex. 058 061 25922 9001 063 065 4352 13882 59347 068 070
27853 13424 053 056 BAA-747 PMB 4 16 0.25 0.125 32 4 0.25 0.25 0.5
8 32 0.5 0.25 >64 32 0.25 C4 >64 ND 1.0 ND ND >64 0.25 1 2
ND ND 1 0.5 ND ND 1 C5 2 16 0.06 0.03 8 1 0.06 0.125 0.5 8 32 0.125
0.25 >64 16 0.125 C6 1 8 0.125 0.06 8 0.25 0.06 0.125 0.125 2 8
0.125 0.03 32 32 0.06 C7 2 ND 1 ND ND 2 ND 1 2 ND ND 0.5 1 ND ND 1
24 4 16 0.125 ND 64 8 0.125 ND 0.5 32 >64 0.25 0.25 >64
>64 0.25 25 1 0.5 0.5 ND 2 1 0.25 ND 2 1 1 1 0.5 ND ND 0.5 26 2
4 1 1 4 1 1 2 2 4 4 2 1 4 2 2 27 2 8 0.5 0.5 8 0.5 0.25 ND 1 4 2
0.5 0.25 8 4 0.5 28 1 8 0.25 0.125 8 1 0.125 ND 0.5 4 4 0.25 0.125
16 4 0.06 29 32 ND 2 ND ND >64 ND ND 8 ND ND 4 4 ND ND 4 30 1 2
1 ND 4 1 1 1 2 2 2 1 2 4 2 1 31 2 16 0.5 ND 16 1 ND 0.5 1 2 2 0.5
0.5 32 16 0.25 32 2 16 0.25 0.125 16 ND 0.06 0.25 0.5 4 4 0.5 0.06
ND 64 0.25 33 2 16 0.25 0.125 64 2 0.03 0.5 0.5 8 8 0.25 0.125 64
32 0.25 34 2 16 0.25 0.125 32 4 0.125 0.125 0.25 4 4 0.25 0.06 32
16 0.125 35 4 16 0.25 0.06 16 0.5 0.125 0.06 0.25 1 2 0.25 0.25
>64 64 0.5 36 8 ND 0.125 ND ND 2 ND 0.125 0.5 ND ND 0.5 2 ND ND
1 37 8 ND 0.06 0.06 ND 16 ND 0.25 0.5 ND ND 0.5 0.5 ND ND 0.125 38
2 16 0.06 0.06 32 1 ND 0.125 0.25 4 4 0.25 0.03 32 8 0.06 39 4 32
0.125 0.06 64 4 ND 0.125 0.5 4 4 0.5 0.03 32 64 0.06 40 8 16 0.125
0.03 16 2 ND 0.25 0.5 4 8 0.5 0.125 >64 64 0.06 41 4 8 0.125
0.06 16 1.5 ND 0.125 0.5 4 4 0.5 0.06 >32 32 0.06 42 4 8 0.5
0.06 32 2 ND 0.25 0.5 2 4 0.5 0.125 >64 32 0.125 43 1 8 0.25
0.06 16 0.5 ND 0.25 0.25 2 2 0.25 0.25 64 32 0.125 44 2 8 0.25 0.03
16 0.5 0.125 0.25 0.5 2 1 0.25 0.06 ND 8 0.06 45 4 16 0.25 0.06 16
1 ND 0.25 0.25 1 1 0.125 0.25 64 64 0.25 46 8 ND 0.125 ND >64 2
ND 0.25 0.5 16 32 0.5 0.125 >64 >64 0.125 47 4 ND 0.25 0.125
ND 0.5 ND 0.5 0.5 ND ND 0.5 0.25 ND ND 0.125 48 4 32 0.125 ND 64 5
ND 0.125 0.25 8 16 0.25 0.25 >64 32 0.125 49 2 16 0.5 0.125 32 2
ND 0.5 0.25 2 2 0.25 0.25 64 64 0.5 50 2 16 0.5 ND ND 1 ND 0.25 0.5
1 2 0.25 0.25 32 16 0.125 51 2 ND 0.5 ND ND 0.25 ND 0.5 0.5 ND ND
0.5 0.25 ND ND 0.5 52 8 16 0.25 ND 64 8 ND 0.25 1 16 16 0.5 0.25
>64 >64 0.25 53 4 32 0.25 0.125 64 4 ND 0.25 0.5 8 8 0.25 0.5
64 64 0.5 54 4 16 0.125 0.06 32 1 ND 0.25 0.5 4 4 0.25 0.25 32 8
0.125 55 2 16 0.25 0.06 16 1 ND 0.25 0.5 4 4 0.125 0.25 8 4 0.125
56 16 ND 0.25 ND ND 16 ND 0.25 0.5 ND ND 0.25 0.125 ND ND 0.125 57
16 ND 0.25 ND ND 8 ND 0.25 0.5 ND ND 0.25 1 ND ND 1 58 4 16 0.25
0.125 64 4 ND 0.25 0.25 2 8 0.25 0.125 64 64 0.03 59 2 ND 0.125
0.06 32 2 0.125 0.25 0.25 4 8 0.25 0.06 32 16 0.03 60 16 ND 0.5 ND
ND ND ND 0.5 1 ND ND ND 1 ND ND 0.5 61 8 ND 0.25 ND ND 32 ND 0.25
0.5 ND ND 0.25 0.25 ND ND 0.25 62 4 32 0.125 ND 64 8 ND 0.125 0.5 8
16 0.5 0.5 >64 >64 0.5 63 4 16 0.25 ND >64 4 ND 0.125 0.5
8 8 0.25 0.125 64 32 0.125 64 8 32 0.125 ND 64 4 ND 0.25 0.25 8 16
0.25 0.25 32 32 0.125 65 4 16 0.25 ND 16 2 ND 0.25 0.5 2 2 0.5 1
>64 >64 0.25 66 8 32 0.125 ND 64 4 ND 0.125 0.5 8 32 0.25
0.06 >64 64 0.125 67 4 16 0.125 0.06 32 1 ND 0.25 0.25 8 16 0.25
0.25 64 16 0.25 68 2 16 0.125 ND 16 1 ND 0.25 0.5 1 1 0.25 0.25
>64 64 0.25 69 4 16 0.06 0.03 16 0.5 0.25 0.25 0.5 4 8 0.25 0.06
>64 64 0.25 70 8 32 0.125 ND 64 8 ND 0.125 0.5 8 32 0.25 0.25 32
16 0.25 71 4 16 0.125 0.125 64 4 0.25 0.25 0.25 8 16 0.25 0.125 64
32 0.125 72 2 8 0.25 0.25 8 0.5 ND 0.25 0.5 4 8 0.25 0.125 64 16
0.25 73 1 2 0.125 0.125 8 2 ND 0.25 0.5 1 1 0.5 0.125 64 16 0.25 74
2 16 0.125 ND 16 2 ND 0.25 0.25 4 4 0.25 0.125 32 32 0.125 75 2 16
0.125 ND 16 1 ND 0.125 0.25 2 2 0.25 0.125 >64 64 0.125 76 8 ND
0.125 ND ND ND ND 0.25 0.5 ND ND 0.5 0.5 ND ND 0.5 77 8 ND 0.25 ND
ND 8 ND 0.5 0.5 ND ND 0.5 0.5 ND ND 1 78 4 ND 0.25 ND ND ND ND 0.25
0.25 ND ND 0.25 0.06 ND ND 0.25 79 2 ND 0.5 ND ND 2 ND 0.5 0.5 ND
ND 0.5 0.25 ND ND 0.25
TABLE-US-00010 TABLE 2A-CONT. Further Additional Microbial Activity
A. baumanii E. coli K. pneumoniae P. aeruginosa ATCC ATCC NCTC ATCC
ATCC CCUG ATCC NCTC BAA- Ex. 058 061 25922 9001 063 065 4352 13882
59347 068 070 27853 13424 053 056 747 80 2 8 0.125 0.03 8 2 0.06
0.25 0.5 2 2 0.25 0.125 64 32 0.125 81 1 16 0.125 0.03 16 4 0.25
0.125 0.25 2 2 0.125 0.125 32 8 0.125 82 2 8 0.06 0.015 32 2 ND
0.125 0.125 4 8 0.125 0.03 64 16 0.125 83 4 16 0.5 0.06 16 1 ND
0.25 0.25 2 8 0.25 0.06 >64 64 0.125 84 8 8 0.125 ND 32 4 ND
0.25 0.5 ND 8 0.25 0.25 >32 32 0.25 85 4 16 0.125 0.06 8 0.5 ND
0.5 0.5 2 4 0.5 0.125 64 64 0.125 86 8 32 0.125 0.06 >64 8 ND
0.5 0.5 ND 8 0.25 0.125 >64 64 0.125 87 4 16 0.125 0.125 16 0.5
ND 0.25 0.5 2 8 0.25 0.125 64 64 0.25 88 2 16 0.25 0.25 64 0.5 ND
0.25 0.5 4 4 0.25 0.125 64 32 0.25 89 16 ND 0.125 ND ND 32 ND 0.25
1 ND ND 0.5 0.25 ND ND 0.5 90 2 16 0.125 0.125 64 4 ND 0.25 0.25 4
16 0.125 0.06 >64 32 0.125 91 4 ND 0.125 ND ND 4 ND 0.25 0.5 ND
ND 0.25 0.125 ND ND 0.25 92 4 ND 0.06 ND ND 8 ND 0.25 1 ND ND 0.25
0.125 ND ND 0.125
[0995] The lipophilicity of the test compounds was estimated using
the calculated value A log P, as described above. The A log P
values are given in Table 2B.
[0996] HK-2 cell IC.sub.50 values were determined as described
herein, and are reported in Table 2B. Values are reported relative
to Polymyxin B.
TABLE-US-00011 TABLE 2B AlogP and IC.sub.50 values HK-2 IC.sub.50
Example AlogP (.mu.g/mL) PMB -6.3 12 C1 -6.2 161 C2 -7.2 316 C3
-4.7 3 C4 -6.5 ND C5 -5.5 29 C6 -5.6 51 C7 -4.5 ND 1 -5.9 7 2 -5.5
ND 3 -4.7 34 4 -4.7 32 5 -5.7 36 6 -3.7 3 7 -3.1 ND 8 -3.1 3 9 -3.1
ND 10 -3.1 4 11 -5.5 ND 12 -5.5 54 13 -6.3 ND 14 -6.3 76 15 -5.5 ND
16 -5.5 32 17 -3.0 ND 18 -3.0 ND 19 -4.6 ND 20 -4.6 10 21 -6.3 83
22 -5.6 17 23 -2.6 ND 24 -6.4 ND 25 -4.6 20 26 -2.7 2 27 -4.9 18 28
-5.8 86 29 -5.9 ND 30 -3.7 4 31 -5.4 ND 32 -5.8 73 33 -5.8 75 34
-6.0 99 35 -5.7 152 36 -5.7 ND 37 -7.1 ND 38 -6.2 255 39 -6.3 337
40 -5.8 ND 41 -5.8 206 42 -5.7 ND 43 -5.7 ND 44 -6.0 ND 45 -5.5 ND
46 -6.8 ND 47 -5.6 ND 48 -6.6 ND 49 -6.2 ND 50 -5.7 ND 51 -5.7 ND
52 -6.5 ND 53 -6.0 ND 54 -5.9 ND 55 -5.5 ND 56 -6.3 ND 57 -6.3 ND
58 -5.9 ND 59 -5.9 ND 60 -6.1 ND 61 -6.1 ND 62 -5.8 ND 63 -5.5 ND
64 -6.1 ND 65 -5.5 ND 66 -5.8 ND 67 -5.8 60 68 -6.1 ND 69 -5.4 ND
70 -6.2 ND 71 -6.1 ND 72 -5.1 ND 73 -5.5 ND 74 -5.9 52 75 -5.5 ND
76 -5.5 ND 77 -5.5 ND 78 -6.2 ND 79 -5.5 ND Example AlogP 80 -5.6
81 -6.0 82 -5.9 83 -5.4 84 -6.0 85 -5.5 86 -5.6 87 -5.6 88 -5.4 89
-5.5 90 -5.6 91 -5.1 92 -5.1
[0997] The in vitro activity of compounds 26 and C7 (FADDI-02)
against resistant bacterial strains was compared. The resistant
strains included including Escherichia coli, Pseudomonas
aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii
strains. The data is provided in Table 2C, where the strains are
identified. The values in Table 2 are MIC (.mu.g/mL).
TABLE-US-00012 TABLE 2C Comparison of in vitro activity between
compounds 26, C7 and PMB Strain 26 C7 (FADDI-02) PMB E. coli CA059
1 2 4 CA060 1 2 4 CA061 2 4 16 K. pneumoniae CA062 2 16 64 CA063 2
8 32 CA064 2 4 8 CA066 1 2 8 CA067 2 64 >64 N655 2 8 32 P.
aeruginosa CA068 2 4 8 CA070 2 2 32 A. baumannii CA053 2 4 >64
CA056 2 4 32
[0998] Further Definitions
[0999] The compounds of formula (I), and optionally the compounds
of formula (II) also, have an N terminal group --X--R.sup.T.
[1000] The group --R.sup.T may be a group --R.sup.5 as described in
WO 2013/072695, a group --R.sup.5 as described in PCT/GB2014/051547
(WO 2014/188178) or a group --R.sup.15 as described in GB
1404301.2, and WO 2015/135976.
[1001] The examples of GB 1404301.2 and WO 2015/135976 describe the
preparation of polymyxin compounds having modified N terminals. For
each of the compounds described and tested, the amino acid residues
at positions 6 and 7 were not modified, thus an L-phenylalanine
residue (polymyxin B) or an L-leucine residue (colistin) is present
at position 6 and an L-leucine residue is present at position
7.
[1002] These examples show that modification to the N terminal
group may be made without limiting biological activity. Further,
those examples show that changes to the N terminal group may
improve biological activity with respect to Polymyxin B. The
modification of the N terminal group may also be associated with a
reduction in toxicity, especially a reduction in
nephrotoxicity.
[1003] The worked examples in the present show that these N
terminal group may be used within compounds that are variant at
position 6 and/or 7 without loss in biological activity. Indeed, in
some instances the changes at the 6 and/or 7 position may provide
compounds having improved biological activity.
[1004] Additional Preferences
[1005] The comments below are preferences for the terminal group
--R.sup.T taking into account the terminal groups described in
PCT/GB2014/051547 (now published as WO 2014/188178) and GB
1404301.2, and additionally or alternatively WO 2015/135976.
[1006] -Q-
[1007] In one embodiment, -Q- is a covalent bond.
[1008] In one embodiment, -Q- is --CH(R.sup.B)--. In this
embodiment, --R.sup.B may be a group -L.sup.A-R.sup.BB, or
--R.sup.B together with --R.sup.17 may form a 5- to 10-membered
nitrogen-containing monocyclic or bicyclic heterocycle, as
described in further detail below.
[1009] Where --R.sup.17 and --R.sup.A together form a
nitrogen-containing heterocycle, the group -Q- is preferably a
covalent bond.
[1010] In one embodiment, -Q- is --CH(R.sup.B)--, and forms part of
a nitrogen-containing heterocycle. In this embodiment, --R.sup.B
may be hydrogen.
[1011] Nitrogen--Containing Heterocycle
[1012] The groups --R.sup.17 and --R.sup.A may, together with the
carbon atoms to which they are attached, form a nitrogen-containing
heterocycle. Similarly, --R.sup.17 and --R.sup.B may, together with
the carbon atoms to which they are attached, form a
nitrogen-containing heterocycle. The nitrogen in the
nitrogen-containing heterocycle refers to the nitrogen atom in
--N(R.sup.16)--.
[1013] The nitrogen-containing heterocycle may be a monocyclic or
bicyclic nitrogen-containing heterocycle. A bicyclic
nitrogen-containing heterocycle has two fused rings. The
nitrogen-containing heterocycle contains a total of 5 to 10 ring
atoms. Where the nitrogen-containing heterocycle is monocyclic it
may have 5 to 7 ring atoms, for example 5 to 6, such as 6, ring
atoms. Where the nitrogen-containing heterocycle is bicyclic it may
have 8 to 10 ring atoms, such as 9 to 10, such as 10, ring atoms.
Each ring in the bicyclic heterocycle may have 5 to 7 ring atoms,
for example 5 or 6, such as 6, ring atoms.
[1014] Where the nitrogen-containing heterocycle is bicyclic, one
ring may be aromatic or partially unsaturated. The ring that is
formed together with the carbon atoms .alpha. and .beta. to the
group --X-- (the first ring) is not aromatic. It is the second
ring, which is the ring fused to the first, that may be aromatic.
The first ring is saturated, except for the carbon ring atoms that
are shared with the second ring (bridge atoms), which may be may be
part of the aromatic ring system of the second ring, for
example.
[1015] Where the nitrogen-containing heterocycle is monocyclic,
each carbon ring atom in --R.sup.17 and --R.sup.A or each carbon
ring atom in --R.sup.17 and --R.sup.B is optionally mono- or
di-substituted with --R.sup.C.
[1016] Where the nitrogen-containing heterocycle is bicyclic, each
carbon ring atom in --R.sup.17 and --R.sup.A or each carbon ring
atom in --R.sup.17 and --R.sup.B is optionally mono- or
di-substituted with --R.sup.D, as appropriate. A carbon ring atom
may be unsubstituted or mono-substituted with --R.sup.D if that
carbon ring atom is part of an aromatic ring system, or is part of
an unsaturated bond.
[1017] The group --R.sup.D includes the group --R.sup.C. In one
embodiment, where the nitrogen-containing heterocycle is bicyclic,
each carbon ring atom in the second ring is optionally mono-or
di-substituted with --R.sup.C and each carbon ring atom in the
first ring in is optionally mono-or di-substituted with
--R.sup.C.
[1018] In one embodiment, the nitrogen-containing heterocycle is a
monocyclic nitrogen-containing heterocycle.
[1019] In one embodiment, the nitrogen-containing heterocycle is a
bicyclic nitrogen-containing heterocycle.
[1020] In one embodiment, one carbon ring atom in the
nitrogen-containing heterocycle is mono- or di-substituted, such as
mono-substituted, with --R.sup.C or substituted with
-L.sup.B-R.sup.BB, where present, for example mono-substituted with
--R.sup.C. In one embodiment, one carbon ring atom in --R.sup.17
and --R.sup.A or --R.sup.17 and --R.sup.B is mono- or
di-substituted, such as mono-substituted, with --R.sup.C, for
example -L.sup.A-R.sup.CC. In these embodiments, the remaining
carbon atoms in the nitrogen-containing heterocycle are
unsubstituted. This embodiment is preferred when the
nitrogen-containing heterocycle is monocyclic.
[1021] Where the nitrogen-containing heterocycle is bicyclic, each
carbon ring atom in the nitrogen-containing heterocycle may be
unsubstituted. Alternatively, where the nitrogen heterocycle is
bicyclic one carbon ring atom in the nitrogen-containing
heterocycle may be mono- or di-substituted, such as
mono-substituted, with --R.sup.C or -L.sup.B-R.sup.BB, such as with
--R.sup.C. For example, where the nitrogen heterocycle is bicyclic
one carbon ring atom in --R.sup.17 and --R.sup.A or --R.sup.17 and
--R.sup.B is mono- or di- substituted, such as mono-substituted,
with --R.sup.C, for example -L.sup.A-R.sup.CC. In these
embodiments, the remaining carbon atoms in the nitrogen-containing
heterocycle are unsubstituted.
[1022] The nitrogen-containing heterocycle may contain further
hetero ring atoms independently selected from nitrogen, oxygen and
sulfur. Where the nitrogen-containing heterocycle is a monocyclic,
the heterocycle optionally contains one further nitrogen, oxygen or
sulfur ring atom. Where the nitrogen-containing heterocycle is a
bicyclic nitrogen-containing heterocycle, the heterocycle
optionally contains one, two or three further heteroatoms, where
each heteroatom is independently selected from the group consisting
of nitrogen, oxygen and sulfur. In a bicyclic system, the further
heteroatoms atoms may be provided in the first or second rings,
such as the first ring.
[1023] In one embodiment, where a further heteroatom is provided,
that heteroatom is nitrogen. In one embodiment, one further
heteroatom is provided, such as one further nitrogen
heteroatom.
[1024] In one embodiment, the nitrogen-containing heterocycle does
not contain a further heteroatom.
[1025] Where two heteroatoms are provided in a ring, they are not
separated by an unsubstituted methylene group (--CH.sub.2--) or a
mono-substituted methylene group (e.g. --CH(R.sup.C)--), and
optionally they are not separated by a di-substituted methylene
group (e.g. --C(R.sup.C).sub.2--).
[1026] Where reference is made to a further nitrogen ring atom, the
ring atom may be provided as a group --NH--, and the nitrogen atom
may be optionally substituted with --R.sup.N or --R.sup.NA, as
appropriate. A further nitrogen ring atom may be unsubstituted if
it is part of an aromatic ring system, or is part of an unsaturated
bond.
[1027] Where reference is made to a further sulfur ring atom, the
sulfur ring atom may be provided as --S--, --S(O)-- or
--S(O).sub.2--, such as --S--.
[1028] Each further nitrogen ring atom is optionally substituted
with a group --R.sup.N, as appropriate, with the exception of a
further nitrogen ring atom that is connected to the carbon that is
.alpha. to the group --X--, which nitrogen ring atom is optionally
substituted with --R.sup.NA. This is shown schematically below for
two exemplary R.sup.15--X-- groups comprising monocyclic
heterocycles containing a further nitrogen ring atom:
##STR00249## [1029] where the ring system on the right has a
nitrogen ring atom that is connected to the carbon atom that is a
to the group --X--. Such a nitrogen atom is optionally substituted
with --R.sup.NA, and is shown substituted with --R.sup.NA. The ring
system on the left has a nitrogen ring atom that is not connected
to the carbon atom that is a to the group --X-- (it is attached to
a carbon .beta. to the group --X--). Such a nitrogen atom is
optionally substituted with --R.sup.N, and is shown substituted
with --R.sup.N. In the exemplary ring structures shown above the
carbon ring atoms are shown to be unsubstituted. As described
herein, carbon ring atoms that are present in --R.sup.17 and
--R.sup.A are optionally mono- or di-substituted.
[1030] It is noted that the definitions for --R.sup.NA do not
encompass groups that would together with the further nitrogen ring
atom form an amide group.
[1031] When a second ring is present and that second ring is an
aromatic ring containing one or more further nitrogen atoms, a
nitrogen atom in the aromatic ring may not be substituted with a
group --R.sup.N, as appropriate.
[1032] Where a further nitrogen ring atom is substituted with
--R.sup.N or --R.sup.NA, as appropriate, each carbon ring atom in
the nitrogen-containing heterocycle may be unsubstituted.
[1033] Where --R.sup.17 and --R.sup.A together form a monocyclic
nitrogen-containing heterocycle, the heterocycle is substituted
with at least one group selected from --R.sup.C, and --R.sup.N,
--R.sup.NA and -L.sup.B-R.sup.BB i.e. at least one of these groups
must be present as a ring substituent at the appropriate position.
Thus, in this embodiment, where the nitrogen-containing heterocycle
is monocyclic and does not contain a further nitrogen atom, at
least one carbon ring atom must be substituted with --R.sup.C or
-L.sup.B-R.sup.BB, where present. Further, in this embodiment,
where the nitrogen-containing heterocycle is monocyclic and
contains a further nitrogen atom, and that nitrogen atom is
unsubstituted, at least one carbon ring atom must be substituted
with --R.sup.C or -L.sup.B-R.sup.BB, where present. If a further
nitrogen atom in the monocyclic nitrogen-containing heterocycle is
substituted with a group --R.sup.N or --R.sup.NA, the carbon ring
atoms may be unsubstituted or optionally mono- or
di-substituted.
[1034] Where --R.sup.17 and --R.sup.B together form a monocyclic
nitrogen-containing heterocycle, the heterocycle is substituted
with at least one group selected from --R.sup.C, and --R.sup.N,
where present. Alternatively the heterocycle is optionally
substituted if --R.sup.A is -L.sup.A-R.sup.AA. In one embodiment,
the monocyclic nitrogen-containing heterocycle is unsubstituted
when the group --R.sup.A is -L.sup.A-R.sup.AA.
[1035] If --R.sup.A is hydrogen, the monocyclic nitrogen-containing
heterocycle must be substituted with at least one group selected
from --R.sup.C, and --R.sup.N, where present. Here, if the
nitrogen-containing heterocycle is monocyclic and does not contain
a further nitrogen atom, at least one carbon ring atom must be
substituted with --R.sup.C. Further, in this embodiment, where the
nitrogen-containing heterocycle is monocyclic and contains a
further nitrogen atom, and that nitrogen atom is unsubstituted, at
least one carbon ring atom must be substituted with --R.sup.C. If a
further nitrogen atom in the monocyclic nitrogen-containing
heterocycle is substituted with a group --R.sup.N, the carbon ring
atoms may be unsubstituted or optionally mono- or
di-substituted.
[1036] Where a nitrogen-containing heterocycle is bicyclic, each
further nitrogen ring atom may be unsubstituted. Alternatively,
where the nitrogen heterocycle is bicyclic one further nitrogen
ring atom may be substituted with a group --R.sup.N, except where
the further nitrogen ring atom is connected to the carbon that is a
to the group --X--, that further nitrogen ring atom is substituted
with a group --R.sup.NA.
[1037] In one embodiment, a monocyclic nitrogen-containing
heterocycle is mono-substituted with --R.sup.C. Thus, one carbon
ring atom in the group --R.sup.17 and --R.sup.A or --R.sup.17 and
--R.sup.B is mono-substituted with --R.sup.C.
[1038] In one embodiment, a monocyclic nitrogen-containing
heterocycle containing a further nitrogen ring atom is
mono-substituted with a group --R.sup.C, --R.sup.N or --R.sup.NA,
for example mono-substituted with a group --R.sup.N or --R.sup.NA
or mono-substituted with a group --R.sup.C. Thus, one ring atom in
the group --R.sup.17 and --R.sup.A or --R.sup.17 and --R.sup.B is
mono-substituted.
[1039] The nitrogen-containing heterocycle may be selected from the
group consisting of pyrrolidine, piperidine, piperazine,
1,4-diazepine, indoline, 1,2,3,4-tetrahydroquinoline,
1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoxaline,
1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine,
1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine,
5,6,7,8-tetrahydro-1,6-naphthyridine and
1,2,3,4-tetrahydro-2,6-naphthyridine. In the bicyclic systems the
aromatic ring, where present, is provided as the second ring.
[1040] The monocyclic nitrogen-containing heterocycles pyrrolidine,
piperidine, piperazine, and 1,4-diazepine are substituted as
discussed above.
[1041] The bicyclic nitrogen-containing heterocycles indoline,
1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline and
1,2,3,4-tetrahydroquinoxaline may be substituted or unsubstituted,
as discussed above.
[1042] A nitrogen-containing heterocycle may be selected from the
group consisting of pyrrolidine, piperidine, piperazine, and
1,4-diazepine.
[1043] In one embodiment, a nitrogen-containing heterocycle is
selected from pyrrolidine, piperidine and piperazine.
[1044] In one embodiment, a bicyclic nitrogen-containing
heterocycle has a first ring selected from pyrrolidine, piperidine
and piperazine fused to a second ring, which may be an aromatic
ring. Examples of the second ring include cyclohexane, benzene and
pyridine ring
[1045] In one embodiment, the groups --R.sup.17 and --R.sup.A
together form a nitrogen heterocycle when -Q- is a covalent bond.
Here, the group --NR.sup.16-- is located on a carbon atom that is
.beta. to the group --X--.
[1046] In another embodiment, the groups --R.sup.17 and --R.sup.A
together form a nitrogen heterocycle when -Q- is not a covalent
bond. Here, the group --NR.sup.16-- is located on a carbon atom
that is .gamma. to the group --X--.
[1047] In one embodiment, --R.sup.17 and --R.sup.A are selected
from *--CH(R.sup.C1)CH(R.sup.C1)CH(R.sup.C1)--,
*--CH(R.sup.C1)CH(R.sup.C1)--, and
*--N(R.sup.NA)CH(R.sup.C1)CH(R.sup.C1)-- where * indicates the
point of attachment to the carbon .alpha. to the group --X--,
--R.sup.C1 is hydrogen or --R.sup.C, and at least one carbon or
nitrogen atom is substituted with --R.sup.C or --R.sup.NA, as
appropriate.
[1048] Exemplary nitrogen-containing heterocycle structures are
given in the --R.sup.15 section below.
[1049] Carbocycle and Heterocycle
[1050] In one embodiment, --R.sup.A and --R.sup.B together form a
5- to 10-membered carbocycle or heterocycle. Here, -Q- is not a
covalent bond. The carbocycle or heterocycle may be substituted or
unsubstituted.
[1051] A carbocycle or a heterocycle may be monocyclic or bicyclic.
A bicyclic carbocycle or a heterocycle has two fused rings.
[1052] The carbocycle or a heterocycle contains a total of 5 to 10
ring atoms. Where the carbocycle or heterocycle is monocyclic it
may have 5 to 7 ring atoms, for example 5 to 6, such as 6, ring
atoms. Where the carbocycle or heterocycle is bicyclic it may have
8 to 10 ring atoms, such as 9 to 10, such as 10, ring atoms. Each
ring in the bicyclic system may have 5 to 7 ring atoms, for example
5 or 6, such as 6, ring atoms.
[1053] Where the carbocycle or heterocycle is bicyclic, one ring
may be aromatic or partially unsaturated. The ring that is formed
together with the carbon atoms .alpha. and .beta. to the group
--X-- (the first ring) is not aromatic. It is the second ring,
which is the ring fused to the first, that may be aromatic. The
first ring is saturated, except for the carbon ring atoms that are
shared with the second ring (bridge atoms), which may be may be
part of the aromatic ring system of the second ring.
[1054] A bicyclic heterocycle is a heterocycle having a heteroatom,
such as N, S, or O in either the first or second ring.
[1055] In one embodiment, a heteroatom is present in the first
ring. In one embodiment, a heteroatom is present in the second
ring.
[1056] The heterocycle includes one or more heteroatoms
independently selected from N, S, and O. In one embodiment
heterocycle includes one or two, such as one heteroatom.
[1057] In one embodiment, the heteroatom is nitrogen.
[1058] In one embodiment, one heteroatom present, such as one
nitrogen heteroatom.
[1059] Where the carbocycle or a heterocycle is monocyclic, each
carbon ring atom in --R.sup.A and --R.sup.B is optionally mono- or
di-substituted with --R.sup.C.
[1060] Where the carbocycle or a heterocycle is bicyclic, each
carbon ring atom in --R.sup.A and --R.sup.B is optionally mono- or
di-substituted with --R.sup.D, which includes --R.sup.C.
[1061] Where reference is made to a nitrogen ring atom, the ring
atom may be provided as a group --NH--, and the nitrogen atom may
be optionally substituted with --R.sup.N or --R.sup.NA, as
appropriate. A further nitrogen ring atom may be unsubstituted if
it is part of an aromatic ring system, or is part of an unsaturated
bond.
[1062] Where reference is made to a sulfur ring atom in the
heterocycle, the sulfur ring atom may be provided as --S--,
--S(O)-- or --S(O).sub.2--, such as --S--.
[1063] In one embodiment, one carbon ring atom in the carbocycle or
heterocycle is mono- or di-substituted, such as mono-substituted,
with --R.sup.C or --R.sup.D, where appropriate. In this embodiment,
the remaining carbon atoms in the carbocycle or heterocycle may be
unsubstituted. This embodiment is preferred when the carbocycle or
heterocycle is monocyclic.
[1064] In one embodiment, the heterocycle has a nitrogen ring atom
and that atom is optionally substituted with --R.sup.N, with the
exception of a nitrogen ring atom that is connected to the carbon
that is a to the group --X--, which nitrogen ring atom is
optionally substituted with --R.sup.NA. In one embodiment, where a
nitrogen ring atom is present in the heterocycle, that ring atom
may be substituted. In this embodiment, the remaining carbon atoms
in the carbocycle or heterocycle may be unsubstituted. This
embodiment is preferred when the heterocycle is monocyclic.
[1065] It is noted that the definitions for --R.sup.NA do not
encompass groups that would together with a nitrogen ring atom form
an amide group.
[1066] When a second ring is present and that second ring is an
aromatic ring containing one or more nitrogen atoms, a nitrogen
atom in the aromatic ring may be substituted with a group
--R.sup.N, as appropriate.
[1067] In one embodiment, a monocyclic carbocycle is selected from
cyclohexane and cyclopentane, which may be substituted as discussed
above.
[1068] In one embodiment, a monocyclic heterocycle is selected from
pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine,
piperazine, 1,4-dioxane, morpholine, thiomorpholine and
1,4-diazepine, which may be substituted as discussed above.
[1069] In one embodiment, a monocyclic carbocycle is selected from
indane and tetralin.
[1070] In one embodiment, a bicyclic heterocycle is selected from
indoline, 1,2,3,4-tetrahydroquinoline,
1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoxaline,
chromane, and dihydrobenzofuran, which may be substituted as
discussed above.
[1071] --R.sup.15
[1072] The group --R.sup.15 together with --X-- may be regarded as
an N terminal substituent group in the compounds of formula (III).
--R.sup.15 contains an amino group which may be a group
--NR.sup.16R.sup.17, or a group --NR.sup.16-- where the nitrogen is
present as a ring atom in a nitrogen-containing heterocycle.
[1073] In the compounds of the invention, the nitrogen group
--NR.sup.16R.sup.17 must be bonded to one methylene group (i.e. a
group --CH.sub.2--). Thus, --R.sup.15 must contain a group
--CH.sub.2NR.sup.16R.sup.17.
[1074] When the nitrogen group --NR.sup.16-- is provided in a
nitrogen-containing heterocycle (i.e. --R.sup.17 and --R.sup.A form
a ring, or --R.sup.17 and --R.sup.B form a ring), the nitrogen atom
must be bonded to one neighboring carbon atom that is part of a
methylene group. This is a requirement for the group --R.sup.15.
However, the other neighboring ring carbon atom is not necessarily
part of a methylene group (it may be a methylene or methine group).
In one embodiment, the nitrogen atom in --NR.sup.16-- is bonded to
two ring methylene groups (i.e. both neighboring ring carbon atoms
are provided in methylene groups). In one embodiment, the nitrogen
atom in --NR.sup.16-- is bonded to a carbon ring atom that is part
of a methylene group and a carbon ring atom that is part of a
methylene or methine group.
[1075] In one embodiment, --R.sup.15 is selected from the groups
listed below. The groups shown below include groups where
--R.sup.17 and --R.sup.A together form a nitrogen-containing
heterocycle.
[1076] In the embodiments below --R.sup.C1 is hydrogen or
--R.sup.C; --R.sup.N1 is hydrogen or --R.sup.NA; --R.sup.D1 is
hydrogen or --R.sup.D; --R.sup.A is hydrogen or
-L.sup.A-R.sup.AA--, --R.sup.B is hydrogen or -L.sup.B-R.sup.BB;
and --R.sup.16 is independently hydrogen or C.sub.1-4 alkyl;
--R.sup.17 is independently hydrogen or C.sub.1-4 alkyl; or
--NR.sup.16R.sup.17 is a guanidine group. As noted above, where -Q-
is a covalent bond --R.sup.A is -L.sup.A-R.sup.AA, and where -Q- is
--CH(R.sup.B)-- one or both of --R.sup.A and --R.sup.B is not
hydrogen. Where the nitrogen-containing heterocycle is monocyclic,
it should be substituted with at least one group selected from
--R.sup.C, and -L.sup.B-R.sup.BB, --R.sup.NA and --R.sup.N.
[1077] In one embodiment, --R.sup.15 is selected from the group
consisting of:
##STR00250##
[1078] In one embodiment, --R.sup.15 is selected from the group
consisting of:
##STR00251##
[1079] In one embodiment, --R.sup.15 is selected from the group
consisting of:
##STR00252##
[1080] In one embodiment, --R.sup.15 is selected from the group
consisting of:
##STR00253##
[1081] In one embodiment, --R.sup.15 is selected from the group
consisting of:
##STR00254##
[1082] In one embodiment, --R.sup.15 is selected from the group
consisting of:
##STR00255##
[1083] In one embodiment, --R.sup.15 is selected from the group
consisting of:
##STR00256##
[1084] In one embodiment, --R.sup.15 is selected from the group
concisting of:
##STR00257##
[1085] In one embodiment, --R.sup.15 is selected from the group
consisting of:
##STR00258##
[1086] In one embodiment, --R.sup.15 is selected from the group
consisting of:
##STR00259##
[1087] In one embodiment, --R.sup.15 is selected from the group
consisting of:
##STR00260##
[1088] In one embodiment, --R.sup.15 is selected from the group
consisting of:
##STR00261##
[1089] In one embodiment, --R.sup.15 is:
##STR00262##
[1090] such as
##STR00263##
[1091] In one embodiment, --R.sup.15 is:
##STR00264##
[1092] such as
[1093] In one embodiment, --R.sup.15 is:
##STR00265##
[1094] such as,
##STR00266##
[1095] In one embodiment, --R.sup.15 is:
##STR00267##
[1096] such as
##STR00268##
[1097] In one embodiment, --R.sup.15 is:
##STR00269##
[1098] such as
##STR00270##
[1099] The structures shown above include examples where --R.sup.15
contains a nitrogen-containing heterocycle. These are compounds
where the groups --R.sup.17 and --R.sup.A, together with the carbon
atoms to which they are attached, form a nitrogen heterocycle. The
nitrogen heterocycles shown above are monocyclic nitrogen
heterocycles.
[1100] Each carbon ring atom in the group --R.sup.17 and --R.sup.A
may be substituted with --R.sup.C1. Where --R.sup.C1 is hydrogen,
the carbon ring atom is unsubstituted.
[1101] A nitrogen ring atom in the group --R.sup.17 and --R.sup.A,
where present, is substituted with --R.sup.N1.
[1102] Where --R.sup.N1 is hydrogen, the nitrogen ring atom is
unsubstituted.
[1103] Where the nitrogen-containing heterocycle contains a further
nitrogen atom, it is preferred that the further nitrogen atom is
substituted with --R.sup.N or --R.sup.NA, as appropriate. In this
embodiment, the ring carbon atoms may be unsubstituted. Where the
nitrogen-containing heterocycle does not contain a further nitrogen
atom, one of the carbon ring atoms is substituted with --R.sup.C or
-L.sup.B-R.sup.BB, and preferably one of the carbon ring atoms
group --R.sup.17 and --R.sup.A is substituted with --R.sup.C.
[1104] The compounds of the invention also include compounds where
--R.sup.17 and --R.sup.A, together with the carbon atoms to which
they are attached, form a bicyclic nitrogen heterocycle. In this
embodiment, it is not necessary for the carbon or nitrogen ring
atoms in --R.sup.17 and --R.sup.A to be substituted (i.e. each of
--R.sup.C and --R.sup.N may be hydrogen).
[1105] Additionally or alternatively to the --R.sup.15 groups shown
above, --R.sup.15 is selected from:
##STR00271##
[1106] Additionally or alternatively to the --R.sup.15 groups shown
above, --R.sup.15 is selected from:
##STR00272##
[1107] Additionally or alternatively to the --R.sup.15 groups shown
above, in one embodiment --R.sup.15 is selected from:
##STR00273##
[1108] such as
##STR00274##
[1109] In one embodiment, --R.sup.A and --R.sup.B may together form
a carbocycle or a heterocycle. The ring atoms of the carbocycle or
heterocycle may be optionally substituted. A carbon ring atom may
be optionally mono- or di-substituted with --R.sup.C. A nitrogen
ring atom, where present, may be optionally substituted with
--R.sup.N, except that a nitrogen ring atom that is connected to
the carbon that is a to the group --X-- is optionally substituted
with --R.sup.NA.
[1110] In the embodiments below --R.sup.C1 is hydrogen or
--R.sup.C; --R.sup.N1 is hydrogen or --R.sup.NA; --R.sup.D1 is
hydrogen or --R.sup.D; and --R.sup.16 is independently hydrogen or
C.sub.1-4 alkyl; --R.sup.17 is independently hydrogen or C.sub.1-4
alkyl; or --NR.sup.16R.sup.17 is a guanidine group. Where the
nitrogen-containing carbocycle heterocycle is monocyclic, it is
optionally substituted with at least one group selected from
--R.sup.C, and --R.sup.NA and --R.sup.N.
[1111] Additionally or alternatively to the --R.sup.15 groups shown
above, in one embodiment --R.sup.15 is selected from:
##STR00275##
[1112] Additionally or alternatively to the --R.sup.15 groups shown
above, in one embodiment --R.sup.15 is selected from:
##STR00276##
[1113] --R.sup.A
[1114] In one embodiment, --R.sup.A is not hydrogen. In one
embodiment, --R.sup.A is -L.sup.A-R.sup.AA. In one embodiment,
--R.sup.A is --R.sup.AA. In these embodiments, --R.sup.B, if
present, may be hydrogen.
[1115] In one embodiment, where --R.sup.A is not hydrogen, for
example where --R.sup.A is -L.sup.A-R.sup.AA or --R.sup.A and
--R.sup.17 together form a nitrogen-containing heterocycle,
--R.sup.15 is an amino-containing group:
##STR00277##
[1116] Where --R.sup.A is -L.sup.A-R.sup.AA it is noted that this
group does not encompass a substituent containing the group
--C(O)N(R.sup.11)--*, where the asterisk indicates the point of
attachment to the carbon that is a to the group --X--. The
inventors have found that where the group --C(O)N(R.sup.11)--* is
present, biological activity is reduced.
[1117] In one embodiment, --R.sup.A and --R.sup.17 together form a
5- to 10-membered nitrogen-containing monocyclic or bicyclic
heterocycle.
[1118] In one embodiment, --R.sup.A and --R.sup.B together form a
5- to 10-membered carbocycle or heterocycle. Here, -Q- is not a
covalent bond.
[1119] In one embodiment, --R.sup.A is not --NHEt or --NEt.sub.2,
for example where R.sup.15--X-- is an N terminal substituent to
Polymyxin B nonapeptide (PMBN).
[1120] In one embodiment, --R.sup.A is not --NHR.sup.PA or
--N(R.sup.PA).sub.2, where each --R.sup.PA is C.sub.1-10 alkyl,
such as C.sub.8-10 alkyl, such as C.sub.1-8 alkyl, such as
C.sub.1-4 alkyl, such as C.sub.1-2 alkyl, for example where
R.sup.15--X-- is an N terminal substituent to Polymyxin B
nonapeptide (PMBN).
[1121] In one embodiment, --R.sup.A is not a group having an oxygen
atom attached to the carbon that is .alpha. to the group --X--. In
one embodiment, --R.sup.A is not a group having a nitrogen atom
attached to the carbon that is a to the group --X--. The
definitions for the group -L.sup.A-R.sup.AA may be construed
accordingly.
[1122] --R.sup.B
[1123] In one embodiment, --R.sup.B, where present, is hydrogen. In
one embodiment, -Q- is a covalent bond and --R.sup.B is accordingly
absent.
[1124] In one embodiment, --R.sup.B is -L.sup.A-R.sup.BB. In one
embodiment, --R.sup.B is --R.sup.BB. In these embodiments,
--R.sup.A may be hydrogen.
[1125] In one embodiment, --R.sup.B is not C.sub.3-10 cycloalkyl,
for example is not cyclohexyl.
[1126] In one embodiment, --R.sup.B and --R.sup.17 together form a
5- to 10-membered nitrogen-containing monocyclic or bicyclic
heterocycle.
[1127] In one embodiment, --R.sup.A and --R.sup.B together form a
5- to 10-membered carbocycle or heterocycle. Here, -Q- is not a
covalent bond.
[1128] Where -Q- is present and is part of a nitrogen-containing
heterocycle and --R.sup.B is -L.sup.A-R.sup.BB, the
nitrogen-containing heterocycle is optionally substituted. Thus
each carbon ring atom in --R.sup.B and --R.sup.17 is optionally
substituted with --R.sup.C, and each nitrogen ring atom in
--R.sup.B and --R.sup.17 is optionally substituted with
--R.sup.N.
[1129] In one embodiment one of --R.sup.A and --R.sup.B is
hydrogen. The other of --R.sup.A and --R.sup.B is therefore not
hydrogen.
[1130] It is noted that the group -L.sup.B-R.sup.BB encompasses a
substituent containing the group --C(O)N(R.sup.11)--*, where the
asterisk indicates the point of attachment to the carbon that is
.beta. to the group --X--.
[1131] --R.sup.C, --R.sup.N and --R.sup.NA
[1132] The groups --R.sup.A and --R.sup.17 or --R.sup.B and
--R.sup.17 may together form a 5- to 10-membered
nitrogen-containing monocyclic or bicyclic heterocycle, and
--R.sup.A and --R.sup.B may together form a 5- to 10-membered
monocyclic or bicyclic carbocycle , or together form a 5- to
10-monocyclic or bicyclic heterocycle. The ring atoms that are
present in the nitrogen-containing heterocycle and the carbocycle
or heterocycle may be substituted or unsubstituted as described
herein.
[1133] The nitrogen-containing heterocycle includes ring atoms that
are part of --R.sup.A and --R.sup.17 or --R.sup.B and --R.sup.17.
Where --R.sup.A and --R.sup.17 or --R.sup.B and --R.sup.17 form a
nitrogen-containing monocyclic or bicyclic heterocycle, each carbon
ring atom in the group --R.sup.A and --R.sup.17 or the group
--R.sup.B and --R.sup.17 may be optionally substituted with
--R.sup.C. These carbon ring atoms may be mono- or di-substituted
with --R.sup.C. In one embodiment, each carbon ring atom is
optionally mono-substituted with --R.sup.C.
[1134] As described herein a nitrogen-containing monocyclic
heterocycle must be substituted. The substituent may be present as
a substituent to a ring atom that is part of --R.sup.A and
--R.sup.17 or --R.sup.B and --R.sup.17. Thus, a group --R.sup.C,
--R.sup.N or --R.sup.NA, where appropriate, is present.
Alternatively the substituent may be present at the carbon to the
group --X-- i.e. -L.sup.B-R.sup.BB is present.
[1135] The nitrogen-containing heterocycle may contain further
nitrogen ring atoms. Each further nitrogen ring atom may be
optionally substituted with --R.sup.N, as appropriate. However,
where the further nitrogen atom is bonded to the carbon that is
.alpha. to the group --X--, that ring nitrogen atom is optionally
substituted with --R.sup.NA.
[1136] In one embodiment, --R.sup.A and --R.sup.B together form a
5- to 10-membered monocyclic or bicyclic carbocycle or heterocycle.
In the monocycle, each ring carbon atom in --R.sup.A and --R.sup.B
is optionally mono- or di-substituted with --R.sup.C. These carbon
ring atoms may be mono- or di-substituted with --R.sup.C. In one
embodiment, each carbon ring atom is optionally mono- substituted
with --R.sup.C. In the bicycle, each ring carbon atom in --R.sup.A
and --R.sup.B is optionally mono- or di-substituted with --R.sup.C.
These carbon ring atoms may be mono- or di-substituted with
--R.sup.D.
[1137] A 5- to 10-membered monocyclic or bicyclic heterocycle may
contain a nitrogen ring atom. Each nitrogen ring atom may be
optionally substituted with --R.sup.N, as appropriate. However,
where the further nitrogen atom is bonded to the carbon that is a
to the group --X--, that ring nitrogen atom is optionally
substituted with --R.sup.NA.
[1138] One of the carbon ring atoms that is part of --R.sup.A and
--R.sup.17, --R.sup.B and --R.sup.17, or --R.sup.A and --R.sup.B
may be substituted with oxo (.dbd.O). A ring carbon atom that is
connected to the nitrogen atom in --N(R.sup.16)-- is not
substituted with oxo. Where such a carbon ring atom is substituted
with oxo it may be joined to a further nitrogen ring atom (where
such is present) to from an amide group. It is noted that a further
nitrogen atom may be connected to the carbon atom that is .alpha.
to the group --X--. The inventors understand that where an amide
group is present within a nitrogen-containing heterocycle as a
substituent to the carbon .beta. to the group --X--, biological
activity is not reduced.
[1139] In one embodiment, where a ring carbon atom is connected to
a further nitrogen ring atom that is connected to the carbon atom
that is .alpha. to the group --X--, that ring carbon atom is not
substituted with oxo.
[1140] Similarly, where such a carbon ring atom is substituted with
oxo it may be joined to a further oxygen ring atom (where such is
present) and an ester group may be formed.
[1141] In one embodiment, the nitrogen-containing heterocycle does
not include a ring amide, carbamate, urea or ester group. In one
embodiment, a further nitrogen ring atom connected to the carbon
that is .alpha. to the group --X-- is not part of an amide,
carbamate or urea group.
[1142] In one embodiment, a further oxygen ring atom connected to
the carbon that is .alpha. to the group --X-- is not part of a
carbamate or ester group.
[1143] Where --R.sup.17 and --R.sup.A form a monocyclic
nitrogen-containing heterocycle, one ring atom (formed together
with the carbon atoms .alpha. and .beta. to the group --X--) must
be substituted. Here the monocyclic nitrogen heterocycle must have
a substituent group present on a carbon ring atom or further
nitrogen ring atom, where present. Thus at least one group
--R.sup.C, --R.sup.N, --R.sup.NA or -L.sup.B-R.sup.BB must be
present as a substituent to the nitrogen-containing heterocycle. In
one embodiment, at least one group --R.sup.C, --R.sup.N and
--R.sup.NA must be present as a substituent to the
nitrogen-containing heterocycle.
[1144] In one embodiment, where --R.sup.17 and --R.sup.A form a
monocyclic nitrogen-containing heterocycle, one or two ring atoms
in --R.sup.17 and --R.sup.A are substituted. The remaining ring
atoms in --R.sup.17 and --R.sup.A are unsubstituted. In one
embodiment, one ring atom in --R.sup.17 and --R.sup.A is
substituted.
[1145] In one embodiment, where R.sup.17 and --R.sup.A form a
monocyclic nitrogen-containing heterocycle, one carbon ring atom in
--R.sup.17 and --R.sup.A is substituted with --R.sup.C, and the
remaining ring atom in --R.sup.17 and --R.sup.A are
unsubstituted.
[1146] In one embodiment, where R.sup.17 and --R.sup.A form a
monocyclic nitrogen-containing heterocycle, and the heterocycle has
a further nitrogen ring atom, the further nitrogen is substituted
with --R.sup.N or --R.sup.NA, as appropriate, and the remaining
ring atoms in --R.sup.17 and --R.sup.A are unsubstituted. In one
embodiment, where R.sup.17 and --R.sup.A form a monocyclic
nitrogen-containing heterocycle, and the heterocycle has a further
nitrogen ring atom, one carbon ring atom in --R.sup.17 and
--R.sup.A is substituted with --R.sup.C, and the remaining ring
atoms in --R.sup.17 and --R.sup.A are unsubstituted.
[1147] Where --R.sup.17 and --R.sup.B form a monocyclic nitrogen
heterocycle, the ring atoms in the ring (formed together with the
carbon atom .beta. to the group --X--) need not be substituted. If
the group --R.sup.A is hydrogen, the monocyclic nitrogen
heterocycle must have a substituent group present on a carbon ring
atom or further nitrogen ring atom, where present. However, if the
group --R.sup.A is not hydrogen, then the carbon ring atoms or
further nitrogen ring atom, where present, need not be
substituted.
[1148] In one embodiment, where --R.sup.17 and --R.sup.B form a
monocyclic nitrogen-containing heterocycle, one or two ring atoms
in --R.sup.17 and --R.sup.B are substituted. The remaining ring
atoms in --R.sup.17 and --R.sup.B are unsubstituted. In one
embodiment, one ring atoms in --R.sup.17 and --R.sup.B is
substituted. In these embodiments, --R.sup.A may be hydrogen.
[1149] In one embodiment, where R.sup.17 and --R.sup.B form a
monocyclic nitrogen-containing heterocycle, one carbon ring atom in
--R.sup.17 and --R.sup.B is substituted with --R.sup.C, and the
remaining ring atoms in --R.sup.17 and --R.sup.B are
unsubstituted.
[1150] In one embodiment, where R.sup.17 and --R.sup.B form a
monocyclic nitrogen-containing heterocycle, and the heterocycle has
a further nitrogen ring atom, the further nitrogen is substituted
with --R.sup.N, and the remaining ring atoms in --R.sup.17 and
--R.sup.B are unsubstituted.
[1151] In one embodiment, where R.sup.17 and --R.sup.B form a
monocyclic nitrogen-containing heterocycle, and the heterocycle has
a further nitrogen ring atom, one carbon ring atom in --R.sup.17
and --R.sup.B is substituted with --R.sup.C, and the remaining ring
atoms in --R.sup.17 and --R.sup.B are unsubstituted.
[1152] A bicyclic nitrogen-containing heterocycle may be
unsubstituted. Here the second fused ring may be regarded as a
substituent to the first ring.
[1153] In one embodiment, where R.sup.17 and --R.sup.A form a
bicyclic nitrogen-containing heterocycle, one carbon ring atom in
--R.sup.17 and --R.sup.A is substituted with --R.sup.D, and the
remaining ring atoms in --R.sup.17 and --R.sup.A are
unsubstituted.
[1154] In one embodiment, where R.sup.17 and --R.sup.A form a
bicyclic nitrogen-containing heterocycle, and the heterocycle has a
further nitrogen ring atom, the further nitrogen is substituted
with --R.sup.N or --R.sup.NA, as appropriate, and the remaining
ring atoms in --R.sup.17 and --R.sup.A are unsubstituted. In one
embodiment, where R.sup.17 and --R.sup.A form a bicyclic
nitrogen-containing heterocycle, and the heterocycle has a further
nitrogen ring atom, one carbon ring atom in --R.sup.17 and
--R.sup.A is substituted with --R.sup.D, and the remaining ring
atoms in --R.sup.17 and --R.sup.A are unsubstituted.
[1155] In one embodiment, a group --R.sup.D is --R.sup.C when it is
provided as a substituent on the first ring of a bicyclic
nitrogen-containing heterocycle.
[1156] --R.sup.D
[1157] In one embodiment, each --R.sup.D is independently selected
from --R.sup.C, halo, --OH, and --NH.sub.2.
[1158] In one embodiment, each --R.sup.D is independently selected
from --R.sup.C and halo.
[1159] In one embodiment, each --R.sup.D is independently
--R.sup.C.
[1160] In one embodiment, each --R.sup.D is independently
-L.sup.C-R.sup.CC.
[1161] A bicyclic nitrogen-containing heterocycle contains a first
ring and a second ring. The first ring is the nitrogen heterocycle
including the carbon atom that is .beta. to the group --X--. In one
embodiment each carbon ring atom in --R.sup.17 and --R.sup.A that
is part of the first ring is optionally mono- or di-substituted
with --R.sup.C.
[1162] The second ring is the ring fused to the first ring. Each
carbon ring atom in --R.sup.17 and --R.sup.A that is part of the
second ring is optionally mono- or di-substituted with
--R.sup.D.
[1163] -L.sup.A-
[1164] The group -L.sup.A- may be a covalent bond.
[1165] Alternatively -L.sup.A- may be a linking group. An asterisk
is used to indicate the point at which the group point of
attachment of the group -L.sup.A to --R.sup.AA. Thus, the remaining
attachment point connects to the carbon that is a to the group
--X--.
[1166] It is noted that -L.sup.A- is not a group
--N(R.sup.11)C(O)--* where the asterisk is the point of attachment
to --R.sup.AA. The inventors have found that such groups have a
poor biological activity, as discussed above.
[1167] In one embodiment, the linking group is selected from
--R.sup.L--*, --O-L.sup.AA-*, --N(R.sup.11)-L.sup.AA-*, and
--C(O)-L.sup.AA-*.
[1168] In one embodiment, the linking group is selected from
--R.sup.L-*, --O-L.sup.AA-*, and --C(O)-L.sup.AA-*.
[1169] In one embodiment, the linking group is selected from
--R.sup.L-*, --N(R.sup.11)-L.sup.AA-*, and --C(O)-L.sup.AA-*.
[1170] In one embodiment, the linking group is selected from
--R.sup.L-* and --C(O)-L.sup.AA-*.
[1171] In one embodiment, the linking group is selected from
--R.sup.L-*, --O-L.sup.AA-*, and --N(R.sup.11)-L.sup.AA-*.
[1172] In one embodiment, the linking group is selected from
--R.sup.L-* and --O-L.sup.AA-*.
[1173] In one embodiment, the linking group is --R.sup.L-*.
[1174] -L.sup.B-
[1175] The group -L.sup.B- may be a covalent bond.
[1176] Alternatively -L.sup.B- may be a linking group.
[1177] An asterisk is used to indicate the point at which the group
point of attachment of the group -L.sup.B- to --R.sup.BB. Thus, the
remaining attachment point connects to the carbon that is .beta. to
the group --X-- (i.e. the carbon atom in --CH(R.sup.B)--).
[1178] In one embodiment, the linking group is selected from
R.sup.L-*, --O-L.sup.AA-*, --OC(O)-L.sup.AA-*,
--N(R.sup.11)-L.sup.AA-*, --C(O)-L.sup.AA-*, and
--C(O)O-L.sup.AA-*.
[1179] In one embodiment, the linking group is selected from
--R.sup.L-*, --O-L.sup.AA-*, --N(R.sup.11)-L.sup.AA-*,
--C(O)-L.sup.AA-*, --C(O)O-L.sup.AA-*, and
--C(O)N(R.sup.11)-L.sup.AA-*.
[1180] In one embodiment, the linking group is selected from
--R.sup.L-*, --O-L.sup.AA-*, --N(R.sup.11)-L.sup.AA-*,
--C(O)-L.sup.AA-*, and --C(O)O-L.sup.AA-*.
[1181] In one embodiment, the linking group is selected from
--R.sup.L-*, --O-L.sup.AA-*, and --N(R.sup.11)-L.sup.AA-*.
[1182] In one embodiment, the linking group is --R.sup.L-*.
[1183] Additionally or alternatively, the linking group is selected
from --N(R.sup.11)S(O)-L.sup.AA-* and
--N(R.sup.11)S(O).sub.2-L.sup.AA-*.
[1184] In one embodiment, the linking group is
--N(R.sup.11)S(O).sub.2-L.sup.AA-*.
[1185] In one embodiment, the linking group is
--N(R.sup.11)S(O).sub.2--*.
[1186] Additionally or alternatively, the linking group is selected
from --S(O)N(R.sup.11)-L.sup.AA-*, and
--S(O).sub.2N(R.sup.11)-L.sup.AA-*.
[1187] In one embodiment, the linking group is
--S(O)N(R.sup.11)-L.sup.AA-*.
[1188] In one embodiment, the linking group is
--S(O).sub.2N(R.sup.11)-L.sup.AA-*.
[1189] -L.sup.C-
[1190] The group -L.sup.C- may be a covalent bond.
[1191] Alternatively -L.sup.C- may be a linking group.
[1192] An asterisk is used to indicate the point at which the group
point of attachment of the group -L.sup.C--to --R.sup.CC. Thus, the
remaining attachment point connects to the carbon ring atom.
[1193] In one embodiment, the linking group is selected from
R.sup.L-*, --O-L.sup.AA-*, --OC(O)-L.sup.AA-*,
--N(R.sup.11)--L.sup.AA-*, --C(O)-L.sup.AA-*, and
--C(O)O-L.sup.AA-*.
[1194] In one embodiment, the linking group is selected from
--R.sup.L-*, --O-L.sup.AA-*, --N(R.sup.11)-L.sup.AA-*,
--C(O)-L.sup.AA-*, --C(O)O-L.sup.AA-*, and
--C(O)N(R.sup.11)-L.sup.AA-*.
[1195] In one embodiment, the linking group is selected from
--R.sup.L-*, --O-L.sup.AA-*, --N(R.sup.11)-L.sup.AA-*,
--C(O)-L.sup.AA-*, and --C(O)O-L.sup.AA-*.
[1196] In one embodiment, the linking group is selected from
--R.sup.L-*, --O-L.sup.AA-*, and --N(R.sup.11)-L.sup.AA-*.
[1197] In one embodiment, the linking group is --R.sup.L-*.
[1198] Additionally or alternatively, the linking group is selected
from --N(R.sup.11)S(O)-L.sup.AA-* and
--N(R.sup.11)S(O).sub.2-L.sup.AA-*.
[1199] In one embodiment, the linking group is
--N(R.sup.11)S(O).sub.2-L.sup.AA-*.
[1200] In one embodiment, the linking group is
--N(R.sup.11)S(O).sub.2--*.
[1201] Additionally or alternatively, the linking group is selected
from --S(O)N(R.sup.11)-L.sup.AA-*, and
--S(O).sub.2N(R.sup.11)-L.sup.AA-*.
[1202] In one embodiment, the linking group is
--S(O)N(R.sup.11)-L.sup.AA-*.
[1203] In one embodiment, the linking group is
--S(O).sub.2N(R.sup.11)-L.sup.AA-*.
[1204] -L.sup.AA-
[1205] In one embodiment, a group -L.sup.AA- is independently a
covalent bond.
[1206] In one embodiment, a group -L.sup.AA- is independently
--R.sup.L.
[1207] -L.sup.N-
[1208] In one embodiment, a group -L.sup.N- is independently a
covalent bond.
[1209] In one embodiment, a group -L.sup.N- is a linking group.
[1210] An asterisk is used to indicate the point of attachment of
the group -L.sup.N- to --R.sup.NN. Thus, the remaining attachment
point connects to the nitrogen ring atom.
[1211] The linking group may be independently selected from
--S(O)-L.sup.AA-*, --S(O).sub.2-L.sup.AA-*, --C(O)-L.sup.AA-* and
--C(O)N(R.sup.11)-L.sup.AA-*. Thus, the linking groups may together
with the nitrogen atom to which they are attached, form
sulfinamide, sulfonamide, amide and urea functionality
respectively.
[1212] In one embodiment, the linking group is independently
selected from --S(O).sub.2-L.sup.AA-*, --C(O)-L.sup.AA-* and
--C(O)N(R.sup.11)-L.sup.AA-*.
[1213] In one embodiment, linking is independently selected from
--S(O).sub.2-L.sup.AA-* and --C(O)N(R.sup.11)-L.sup.AA-*.
[1214] It is noted that the group -L.sup.N- is present only as a
substituent to a further ring nitrogen atom that is not connected
to the carbon that is a to the group --X--. Where a further ring
nitrogen atom is connected to the carbon that is a to the group
--X--, it is optionally substituted with --R.sup.L--R.sup.NN. The
group --R.sup.L--R.sup.NN does not allow for sulfinamide,
sulfonamide, amide and urea groups connected to the carbon that is
a to the group --X--. The presence of sulfinamide, sulfonamide,
amide and urea functionality is believed to be tolerated at other
ring positions.
[1215] --R.sup.L--
[1216] In one embodiment, each --R.sup.L-- is independently
selected from C.sub.1-12 alkylene, C.sub.2-12 heteroalkylene,
C.sub.3-10 cycloalkylene and C.sub.5-10 heterocyclylene.
[1217] However, where -L.sup.AA- is connected to a group C.sub.1-12
alkyl, --R.sup.L-- is not C.sub.1-12 alkylene. In a further
embodiment, where -L.sup.AA- is connected to a group C.sub.1-12
alkyl, --R.sup.L-- is not C.sub.1-12 alkylene and it is not
C.sub.2-12 heteroalkylene.
[1218] Where --R.sup.L-- is a heteroalkylene it may be connected to
--R.sup.AA, --R.sup.BB, --R.sup.CC, or --R.sup.NN via a heteroatom
of the heteroalkylene group, such as N, O or S, where present, or a
carbon atom of the heteroalkylene group. The other point of
connection is made via a carbon atom of the heteroalkylene group,
for example where the heteroalkylene is attached to a carbon atom
or a heteroatom, such as N, O or S. The other point of connection
may be made via a heteroatom of the heteroalkylene group, for
example where the heteroalkylene is attached to a carbon atom.
However, it is preferred that the other point of connection is made
via a carbon atom of the heteroalkylene group, particularly where
--R.sup.L-- is present in a group -L.sup.AA-.
[1219] Where --R.sup.L-- is a heterocyclylene it may be connected
to --R.sup.AA, --R.sup.BB, --R.sup.CC, or --R.sup.NN via a ring
nitrogen heteroatom of the heterocyclylene group, where present, or
a carbon ring atom of the heterocyclylene group. The other point of
connection is made via a ring carbon atom of the heterocyclylene
group, for example where the heterocyclylene is attached to a
carbon atom or a heteroatom, such as N, O or S. The other point of
connection may be made via a ring nitrogen heteroatom of the
heterocyclylene group, for example where the heterocyclylene is
attached to a carbon atom.
[1220] In one embodiment, a group --R.sup.L-- is independently
selected from C.sub.1-12 alkylene, and C.sub.2-12
heteroalkylene.
[1221] In one embodiment, a group --R.sup.L-- is independently
selected from C.sub.1-12 alkylene and C.sub.3-10 cycloalkylene.
[1222] In one embodiment, a group --R.sup.L-- is independently
C.sub.1-12 alkylene.
[1223] The group --R.sup.L-- may be substituted with one or more
groups --R.sup.S. Thus, each C.sub.1-12 alkylene, C.sub.2-12
heteroalkylene, C.sub.3-10 cycloalkylene and C.sub.5-10
heterocyclylene is optionally substituted with one or more groups
--R.sup.S. The specified groups may be unsubstituted or
mono-substituted. The group --R.sup.S may be present as a
substituent to a carbon atom. A carbon atom may be optionally mono-
or di-substituted with --R.sup.S.
[1224] Where a nitrogen atom is present in a group, such as in a
heterocyclylene group or a heteroalkylene group, that nitrogen atom
may be optionally substituted with a group --R.sup.12.
[1225] In one embodiment, a group --R.sup.L-- is unsubstituted.
[1226] In one embodiment, a C.sub.1-12 alkylene group is selected
from C.sub.1-6 alkylene, C.sub.1-4 alkylene, C.sub.2-6 alkylene,
and C.sub.2-4 alkylene.
[1227] In one embodiment, an alkylene group is linear.
[1228] In one embodiment, a C.sub.1-12 alkylene group is selected
from --CH.sub.2--, --CH.sub.2CH.sub.2--, and --CH(CH.sub.3)--.
[1229] In one embodiment, a C.sub.1-12 alkylene group is
--CH.sub.2--, for example when it is connected to a cycloalkyl,
heterocyclyl, or aryl group.
[1230] In one embodiment, a C.sub.2-12 heteroalkylene group is
selected from C.sub.2-6 heteroalkylene, and C.sub.2-4
heteroalklyene.
[1231] In one embodiment, a C.sub.2-12 heteroalkylene group is
selected from --CH.sub.2O--*, --CH.sub.2CH.sub.2O--*,
--CH.sub.2NH--*, --CH.sub.2CH.sub.2NH--*, --CH.sub.2N(R.sup.12)--*,
and --CH.sub.2CH.sub.2N(R.sup.12)--*, where the asterisk indicates
the point of attachment to --R.sup.AA, --R.sup.BB, --R.sup.CC, or
--R.sup.NN. Thus, a heteroatom in the heteroalkylene group may be
connected to --R.sup.AA, --R.sup.BB, --R.sup.CC, or --R.sup.NN. The
other point of connection may be made via a carbon atom of the
heteroalkylene group.
[1232] Where an S atom is present in the heteroalkylene group, it
may be in the form S, S(O) or S(O).sub.2.
[1233] In one embodiment, the C.sub.3-10 cycloalkylene is selected
from cyclopropylene, cyclopentylene and cyclohexylene. In one
embodiment, the C.sub.3-10 cycloalkylene is cyclohexylene.
[1234] In one embodiment, the C.sub.5-10 heterocyclylene is
C.sub.5-6 heterocyclylene.
[1235] In one embodiment, the C.sub.5-10 heterocyclylene is
selected from piperidinene, piperazinene, morpholinene and
thiomorpholinene. The heterocyclylene may be connected to
--R.sup.AA, --R.sup.BB, --R.sup.CC, or --R.sup.NN via a ring carbon
or ring nitrogen atom. The other point of connection may be made
via a carbon atom of the heterocyclylene group.
[1236] A nitrogen atom, where present, is optionally substituted
with --R.sup.12.
[1237] Where an S atom is present in the heterocyclylene group, it
may be in the form S, S(O) or S(O).sub.2.
[1238] --R.sup.AA, --R.sup.BB, --R.sup.CC, and --R.sup.NN
[1239] Each of --R.sup.AA, --R.sup.BB, --R.sup.CC, and --R.sup.NN,
where present, is independently selected from C.sub.1-12 alkyl,
C.sub.3-10 cycloalkyl, C.sub.4-10 heterocyclyl, and C.sub.5-12
aryl.
[1240] In one embodiment, a C.sub.1-12 alkyl group is selected from
C.sub.1-6 alkyl, C.sub.1-7 alkyl, C.sub.1-4 alkyl, C.sub.2-6 alkyl,
C.sub.2-4 alkyl, C.sub.3-10 alkyl, C.sub.3-7 alkyl, C.sub.4-10
alkyl and C.sub.6-10 alkyl.
[1241] In one embodiment, an alkyl group is linear.
[1242] In one embodiment, an alkyl group is branched.
[1243] In one embodiment, the C.sub.1-12 alkyl group does not
include C.sub.8 alkyl.
[1244] In one embodiment, a C.sub.3-10 cycloalkyl group is
C.sub.3-6 cycloalkyl or C.sub.5-6 cycloalkyl.
[1245] In one embodiment, a C.sub.3-10 cycloalkyl group is
cyclohexyl.
[1246] In one embodiment, a C.sub.4-10 heterocyclyl group is
selected from C.sub.5-10 heterocyclyl, C.sub.6-10 heterocyclyl,
C.sub.5-7 heterocyclyl and C.sub.5-6 heterocyclyl.
[1247] In one embodiment, a C.sub.4-10 heterocyclyl group is
selected from tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl,
morpholinyl, thiomorpholinyl, piperidinyl and piperazinyl.
[1248] In one embodiment, a C.sub.4-10 heterocyclyl group is
selected from tetrahydropyanyl, morpholinyl, piperidinyl and
piperazinyl.
[1249] Where an S atom is present in a heterocyclyl group, it may
be in the form S, S(O) or S(O).sub.2.
[1250] A nitrogen atom, where present, is optionally substituted
with --R.sup.12.
[1251] A heterocyclyl group may be connected via a ring nitrogen
heteroatom atom or a ring carbon atom. Where the heterocyclyl group
is a substituent to a nitrogen atom (e.g. present in the group
--R.sup.L--), the heterocyclyl group is connected to that nitrogen
atom via a ring carbon atom.
[1252] An aryl group, particularly a heteroaryl group such as
indole, may be connected via a ring nitrogen heteroatom atom or a
ring carbon atom. Where the heteroaryl group is a substituent to a
nitrogen atom, the heteroaryl group is connected to that nitrogen
atom via a ring carbon atom. Typically, the aryl group is connected
via a ring carbon atom.
[1253] In one embodiment, the C.sub.5-12 aryl is selected from
C.sub.6-12 carboaryl and C.sub.5-12 heteroaryl.
[1254] In one embodiment, the C.sub.5-12 aryl is selected from
phenyl, pyridyl, and naphthyl, optionally together with
1,3-benzodioxolyl and pyridonyl.
[1255] In one embodiment, the C.sub.6-12 carboaryl is selected from
phenyl, naphthyl, chromanyl, iso-chromanyl and 1,3-benzodioxolyl.
The chromanyl, iso-chromanyl and 1,3-benzodioxolyl groups are
connected via an aromatic ring carbon atom. Further discussion
about the meaning of the term carboaryl is provided below with
reference to the group -G.
[1256] In one embodiment, the C.sub.5-12 carboaryl is selected from
phenyl and naphthyl,
[1257] In one embodiment, the C.sub.5-12 heteroaryl is selected
from C.sub.5-10 heteroaryl and C.sub.5-6 heteroaryl.
[1258] In one embodiment, the C.sub.5-12 heteroaryl is selected
from the group consisting of independently furanyl, thienyl,
pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,
quinolinyl, isoquinolinyl, indolyl and pyridonyl.
[1259] Further discussion about the meaning of the term heteroaryl
is provided below with reference to the group -G.
[1260] Each C.sub.1-12 alkyl, C.sub.3-10 cycloalkyl, C.sub.4-10
heterocyclyl, and C.sub.5-12 aryl group is optionally substituted
with --R.sup.S at carbon and --R.sup.12 at nitrogen, where present.
Each group may have one, two, three or more groups --R.sup.S. In
one embodiment, a heterocyclyl group or a heteroaryl group may have
one, two, three or more groups --R.sup.12.
[1261] In one embodiment, a group is mono-subsituted.
[1262] In one embodiment, a group is unsubstituted.
[1263] The group --R.sup.S is present as a substituent to a carbon
atom. A carbon atom may be optionally mono- or di-substituted with
--R.sup.S.
[1264] Where a nitrogen atom is provided, such as in a heterocyclyl
group or a heteroaryl group, that nitrogen may be optionally
substituted with a group --R.sup.12.
[1265] In one embodiment, --R.sup.AA is independently selected from
C.sub.1-12 alkyl and C.sub.5-12 aryl.
[1266] In one embodiment, --R.sup.AA is independently C.sub.1-12
alkyl. In one embodiment, --R.sup.AA is independently C.sub.2-12
alkyl, such as C.sub.3-12 alkyl.
[1267] In one embodiment, --R.sup.AA is independently C.sub.5-12
aryl.
[1268] In one embodiment, --R.sup.BB is independently selected from
C.sub.1-12 alkyl, C.sub.4-10 heterocyclyl, and C.sub.5-12 aryl, for
example when -L.sup.B- is a covalent bond, or for example when
--R.sup.A is hydrogen.
[1269] In one embodiment, --R.sup.BB is independently selected from
C.sub.1-12 alkyl, C.sub.3-10 cycloalkyl, C.sub.4-10 heterocyclyl,
and C.sub.5-12 aryl, for example when --R.sup.B is a substituent to
a heterocycle ring carbon atom.
[1270] In one embodiment, --R.sup.BB is independently selected from
C.sub.1-12 alkyl and C.sub.5-12 aryl.
[1271] In one embodiment, --R.sup.BB is independently C.sub.1-12
alkyl. In one embodiment, --R.sup.BB is independently C.sub.2-12
alkyl, such as C.sub.3-12 alkyl.
[1272] In one embodiment, --R.sup.BB is independently C.sub.5-12
aryl.
[1273] In one embodiment, a group --R.sup.NN is independently
selected from C.sub.1-12 alkyl and C.sub.5-12 aryl.
[1274] In one embodiment, --R.sup.NN is independently C.sub.1-12
alkyl. In one embodiment, --R.sup.NN is independently C.sub.2-12
alkyl, such as C.sub.3-12 alkyl.
[1275] In one embodiment, --R.sup.NN is independently C.sub.5-12
aryl.
[1276] --R.sup.S
[1277] The group --R.sup.S is an optional substituent to each
C.sub.1-12 alkyl, C.sub.3-10 cycloalkyl, C.sub.4-10 heterocyclyl,
C.sub.5-12 aryl, C.sub.1-12 alkylene, C.sub.2-12 heteroalkylene,
C.sub.3-10 cycloalkylene and C.sub.5-10 heterocyclylene group.
Where a group is optionally substituted, it may be optionally
substituted with one or more groups --R.sup.S. A group may be
optionally mono-substituted with --R.sup.S.
[1278] The group --R.sup.S is an optional substituent to a carbon
atom. A carbon atom may be mono-, di- or tri-substituted.
[1279] In one embodiment, each --R.sup.S, where present, is
independently selected from --OH, --OR.sup.12, halo, --R.sup.12,
--NHR.sup.12, --NR.sup.12R.sup.13, --C(O)R.sup.12, --COOH and
--COOR.sup.12.
[1280] In one embodiment, each --R.sup.S, where present, is
independently selected from --OR.sup.12, halo, --R.sup.12,
--NHR.sup.12, --NR.sup.12R.sup.13, --C(O)R.sup.12, --COOH and
--COOR.sup.12.
[1281] In one embodiment, each --R.sup.S, where present, is
independently selected from --OR.sup.12, halo, and --R.sup.12.
[1282] Where --R.sup.S is a substituent to an alkyl group,
--R.sup.S is not --R.sup.12.
[1283] Where --R.sup.S is halo it may be selected from fluoro,
chloro, bromo and iodo, such as chloro and bromo, such as
chloro.
[1284] In one embodiment, where a carbon atom is di-substituted
with --R.sup.S, these groups may together with the carbon to which
they are attached form a C.sub.3-6 carbocycle or a C.sub.5-6
heterocycle, where the carbocycle and the heterocycle are
optionally substituted with one or more groups --R.sup.12. Where an
S atom is present in the heterocycle group, it may be in the form
S, S(O) or S(O).sub.2.
[1285] In one embodiment, a C.sub.3-6 carbocycle is cyclopentane or
cyclohexane, such as cyclohexane.
[1286] In one embodiment, a C.sub.5-6 heterocycle is selected from
piperidine, piperazine, morpholine, thiomorpholine, tetrahydrofuran
and tetrahydropyran.
[1287] --R.sup.12 and --R.sup.13
[1288] Each --R.sup.12 and --R.sup.13 is independently C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, phenyl or benzyl.
[1289] Where --R.sup.12 and --R.sup.13 are both attached to N, they
may together with the N atom form a 5- or 6-membered heterocycle,
such as pyrrolidine, piperazine, piperidine, thiomorpholine or
morpholine. The heterocyclic ring is optionally substituted with
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, phenyl or benzyl.
[1290] In one embodiment, a --R.sup.12 or --R.sup.13 group is
independently C.sub.1-6 alkyl, phenyl or benzyl.
[1291] In one embodiment, a --R.sup.12 or --R.sup.13 group is
independently C.sub.1-6 alkyl.
[1292] In one embodiment, the C.sub.1-6 alkyl is selected from
methyl and ethyl.
[1293] In one embodiment, the C.sub.1-6 haloalkyl is
--CF.sub.3.
[1294] --R.sup.11
[1295] In one embodiment, a group --R.sup.11 is independently
selected from hydrogen, methyl and ethyl.
[1296] In one embodiment, --R.sup.11 is independently hydrogen.
[1297] Embodiments Relating to Compounds (I) and (II) from WO
2014/188178
[1298] The compounds of the present case may use a group --R.sup.5
from compounds (I) and (II) of WO 2014/188178 as a group
--R.sup.T.
[1299] --X-- and --R.sup.5
[1300] The compounds of formula (I) do not encompass the deacylated
versions of Polymyxin B (Deacylpolymyxin B-DAPB), D, E
(Deacylcolistin-DAC) or M, or Circulin A. The compounds of formula
(I) do not encompass the nonapeptide versions of Polymyxin B
(PMBN), D, E or M, or Circulin A.
[1301] In one embodiment, --X-- and --R.sup.5 together are not an
.alpha.-amino acid residue, for example when -A- is a covalent
bond. An .alpha.-amino acid residue is a group where --X-- is
--C(O)-- and --R.sup.5 has a group --NR.sup.6R.sup.7 (such as
--NH.sub.2) as a substituent to the carbon atom that is .alpha. to
the group --X--.
[1302] In one embodiment, --X-- and --R.sup.5 together are not Thr,
Ser, .alpha.,.gamma.-diaminobutyric acid (Dab) or
.alpha.,.beta.-diaminopropionic acid (Dap) residues.
[1303] In one embodiment, for example where the core of the
compound of formula (I) is Polymyxin B, X and R.sup.5 together are
not Lys, Arg, Dap, Ser, Phe, Trp, Leu or Ala residues.
[1304] In one embodiment, --X-- and --R.sup.5 together are not Lys,
Arg, Dap, Ser, Phe, Trp, Leu, Ala .alpha.,.gamma.-diaminobutyric
acid (Dab) or .alpha.,.beta.-diaminopropionic acid (Dap)
residues.
[1305] In one embodiment, --X-- and --R.sup.5 together are not Ala,
Ser, Thr, Val, Leu, Ile, Pro, Phe, Tyr, Trp, His, Lys or Arg
residues.
[1306] In one embodiment, --X-- and --R.sup.5 together are not Ala,
Ser, Thr, Val, Leu, Ile, Pro, Phe, Tyr, Trp, His, Lys,
Arg,.alpha.,.gamma.-diaminobutyric acid (Dab) or
a,8-diaminopropionic acid (Dap) residues.
[1307] In one embodiment, --X-- and --R.sup.5 together are not an
.alpha.-amino acid, for example a D or L .alpha.-amino acid, for
example a L .alpha.-amino acid.
[1308] In one embodiment, --R.sup.5 is not diaminophenyl, for
example, 3,5-diaminophenyl when --X-- is --C(O)--.
[1309] --R.sup.5
[1310] In one embodiment, --R.sup.5 is G-L.sup.2-L.sup.1-.
[1311] --R.sup.5 may be G-L.sup.1-, for example where -L.sup.2- is
a covalent bond.
[1312] --R.sup.5 may be G-L.sup.2-, for example where -L.sup.1- is
a covalent bond.
[1313] --R.sup.5 may be -G, for example where -L.sup.1- and
-L.sup.2- are covalent bonds.
[1314] In one embodiment, --R.sup.5 is D-L.sup.1-.
[1315] --R.sup.5 may be -D, for example where -L.sup.1- is a
covalent bond.
[1316] In one embodiment, --R.sup.5 has one, two or three hydroxyl
and/or --NR.sup.6R.sup.7 groups. These groups may be provided on
any group within --R.sup.5, including -G, -D, -L.sup.1- and
-L.sup.2-. In one embodiment, these groups are provided as
substituents to -G, -D, and -L.sup.1-.
[1317] It is noted that the hydroxyl and --NR.sup.6R.sup.7 groups
are optionally substituents to the group D-L.sup.1-.
[1318] Where the hydroxyl and --NR.sup.6R.sup.7 substituents are
discussed below, they may be referred to as substituents to
--R.sup.5.
[1319] In one embodiment, the one, two or three hydroxyl and/or
--NR.sup.6R.sup.7 groups are optional substituents to --R.sup.5.
This may be the case where -L.sup.1- is a nitrogen-containing
C.sub.2-12 heteroalkylene, and/or -L.sup.2- is a
nitrogen-containing C.sub.4-10 heterocyclylene, and/or -D is a
nitrogen-containing C.sub.4-10 heterocyclyl.
[1320] In one embodiment, --R.sup.5 has at least 5, at least 6, at
least 7 or at least 8 carbon atoms present.
[1321] In one embodiment, --R.sup.5 has 1, 2, or 3 nitrogen atoms
present. In one embodiment, the nitrogen atom is a basic nitrogen
atom. The nitrogen atom may be present as NH. In one embodiment,
--R.sup.5 has 1, 2, or 3 oxygen atoms present.
[1322] In one embodiment, --R.sup.5 is not aminocyclohexyl, for
example when -A- is a covalent bond, --X-- is --C(O)-- and
--R.sup.1, --R.sup.2 and --R.sup.3 are amino acid residues of
polymyxin B.
[1323] Okimura et al. describe Polymyxin B nonapeptide compounds
having aminocyclohexyl groups at the N terminal. These compounds
are not described for use in combination with an active agent,
[1324] In one embodiment, --R.sup.5 is not an aminocyclohexyl group
selected from the groups consisting of cis-2-aminocylcohexyl,
trans-2-aminocylcohexyl, cis-3-aminocyclohexyl,
cis-4-aminocylcohexyl, and trans-4-aminocylcohexyl. Additionally or
alternatively, --R.sup.5 is not trans-3-aminocylcohexyl.
[1325] Linker: -L.sup.2-L.sup.1- and -L.sup.1-
[1326] Within the groups G-L.sup.2-L.sup.1- and D-L.sup.1-,
-L.sup.2-L.sup.1- and -L.sup.1- may be regarded as linkers
connecting the group --X-- to -G or -D. The linker may be absent,
for example where -L.sup.1- and -L.sup.2- are covalent bonds.
[1327] -L.sup.2-L.sup.1- in G-L.sup.2-L.sup.1-
[1328] In one embodiment, -L.sup.1- and -L.sup.2- are both covalent
bonds. Thus, the group -G is connected directly to --X--. Here, the
hydroxyl or amino groups (such as one, two or three hydroxyl and/or
--NR.sup.6R.sup.7 groups) must be present on -G.
[1329] Where -L.sup.1- is a nitrogen-containing C.sub.2-12
heteroalkylene and/or -L.sup.2- is a nitrogen-containing C.sub.4-10
heterocyclylene, it is not necessary for G-L.sup.2-L.sup.1- to be
substituted with one, two or three hydroxyl and/or
--NR.sup.6R.sup.7 groups.
[1330] -L.sup.1- in D-L.sup.1-
[1331] In one embodiment, -L.sup.1- is a covalent bond. Thus, the
group -D is connected directly to --X--.
[1332] Where the group D-L.sup.1- is substituted with a hydroxyl
group or an amino group (such as one, two or three hydroxyl and/or
--NR.sup.6R.sup.7 groups), the groups must be present on -D.
[1333] Where -L.sup.1- is a nitrogen-containing C.sub.2-12
heteroalkylene and/or -D is a nitrogen-containing C.sub.4-10
heterocyclyl it is not necessary for D-L.sup.1- to be substituted
with one, two or three hydroxyl and/or --NR.sup.6R.sup.7
groups.
[1334] -L.sup.1-
[1335] In one embodiment, -L.sup.1- is a covalent bond or a
C.sub.1-12 alkylene group.
[1336] In one embodiment, -L.sup.1- is a covalent bond.
[1337] In one embodiment, -L.sup.1- is a C.sub.1-12 alkylene group
or a C.sub.2-12 heteroalkylene group.
[1338] In one embodiment, -L.sup.1- is a C.sub.1-12 alkylene
group.
[1339] In one embodiment, -L.sup.1- is C.sub.1-12 alkylene, for
example C.sub.1-6, C.sub.1-4 or C.sub.1-2 alkylene.
[1340] In one embodiment, -L.sup.1- is --CH.sub.2- or
--CH.sub.2CH.sub.2--.
[1341] In one embodiment, -L.sup.1- is C.sub.2-12 alkylene, for
example C.sub.2-6 or C.sub.2-4 alkylene.
[1342] In one embodiment, -L.sup.1- is C.sub.3-12 alkylene, for
example C.sub.3-6, C.sub.4-12, C.sub.5-12 or C.sub.6-12
alkylene.
[1343] The alkylene group is a saturated, aliphatic alkylene
group.
[1344] The alkylene group may be a linear or a branched alkylene
group. In one embodiment, the alkylene group is linear.
[1345] Where -L.sup.1- is an alkylene group and R.sup.5 is
substituted with one, two or three hydroxyl and/or
--NR.sup.6R.sup.7 groups, one or more of the substituents may be
substituents to the alkylene group.
[1346] In one embodiment, the alkylene group has one, two or three
substituents.
[1347] In one embodiment, the alkylene group has one or two
substituents, such as one substituent.
[1348] In one embodiment, the number of substituents on the
alkylene group is no greater than the number of carbon atoms in the
alkylene group. Thus, where -L.sup.1- is a C.sub.2 alkylene group
it may be substituted with no more than two substituents.
[1349] Additional substituents, where present, may be located on -G
or -D, where appropriate.
[1350] In one embodiment, the alkylene group is unsubstituted.
[1351] In one embodiment, -L.sup.1- is C.sub.2-12 heteroalkylene. A
heteroalkylene group is an alkylene group where one or more, such
as two or three, or more, of the carbon atoms is replaced with a
heteroatom selected from N, O and S. The superscript e.g. 4 in
C.sub.4 refers to the total number of carbon atoms and heteroatoms.
The heteroatom of the heteroalkylene group is understood not to be
a pendant amino, hydroxyl or thiol group.
[1352] In one embodiment, the heteroalkylene group contains one or
two heteroatoms, for example one or two nitrogen atoms, such as one
or two --NH--.
[1353] In one embodiment, heteroalkylene group is a
nitrogen-containing heteroalkylene group.
[1354] The heteroatom may be provided as an interruption of the
alkylene chain e.g. --CH.sub.2--NH--CH.sub.2--.
[1355] The heteroatom may be provided as a terminal group for
connection to --X--, -L.sup.2-, -G or -D, for example
--CH.sub.2--CH.sub.2--NH-- or --NH--CH.sub.2--CH.sub.2--. In these
embodiments, the heteroatom is bonded to a carbon atom in --X--,
-L.sup.2-, -G or -D.
[1356] In one embodiment, the heteroatom of the heteroalkylene
group is not covalently bonded to the group --X--.
[1357] In one embodiment, the heteroatom of the heteroalkylene
group is not covalently bonded to the group -L.sup.2-, -G or -D,
where present. In an alternative embodiment, a heteroatom of the
heteroalkylene group, such as --NH--, is covalently bonded to the
group -L.sup.2-, -G or -D, where present.
[1358] In one embodiment, -L.sup.1- is C.sub.2-12 heteroalkylene,
for example C.sub.2-6, C.sub.2-4, C.sub.3-6, C.sub.3-12, C.sub.4-6
or C.sub.4-12 heteroalkylene.
[1359] The heteroalkylene group is a saturated, aliphatic
heteroalkylene group.
[1360] The heteroalkylene group may be a linear or a branched
heteroalkylene group. In one embodiment, the heteroalkylene group
is linear.
[1361] In one embodiment, -L.sup.1- is
--NH--CH.sub.2CH.sub.2--NH--CH.sub.2--.
[1362] In one embodiment, -L.sup.1- is
--CH.sub.2--NH--CH.sub.2CH.sub.2--.
[1363] In one embodiment, the heteroalkylene group is
unsubstituted.
[1364] In one embodiment, the heteroalkylene group is substituted,
for example with one or two hydroxyl and/or --NR.sup.6R.sup.7
groups, such as one hydroxyl or --NR.sup.6R.sup.7 group. The
substituents are provided on the carbon atoms within the
heteroalkylene group
[1365] In one embodiment, the number of substituents on the
heteroalkylene group is no greater than the number of carbon atoms
in the heteroalkylene group.
[1366] Where the heteroalkylene group is substituted, the
substituents are preferably not provided on a carbon atom that is
covalently bonded to a heteroatom of the heteroalkylene group.
[1367] Where the heteroalkylene group is substituted, the
substituents may be provided on a carbon atom that is not bonded to
a heteroatom.
[1368] -L.sup.2-
[1369] In one embodiment, -L.sup.2- is a covalent bond.
[1370] In one embodiment, -L.sup.2- is a C.sub.4-10 heterocyclylene
group, for example when -L.sup.1- is a C.sub.1-12 alkylene
group.
[1371] In one embodiment, -L.sup.2- is a C.sub.4-7 heterocyclylene
group, for example a C.sub.5-7 or C.sub.5-6 heterocyclylene
group.
[1372] In one embodiment, the C.sub.4-10 heterocyclylene contains
one or two heteroatoms selected from N, S and O. Where a S atom is
present, it may be in the form S, S(O) or S(O).sub.2. Where an N
atom is present it may be in the form NH or NR, where --R is
C.sub.1-4 alkyl, such as methyl or ethyl.
[1373] In one embodiment, the heterocyclylene group is a
nitrogen-containing heterocyclylene.
[1374] The heterocyclylene group may contain one or two nitrogen
atoms. Each nitrogen atom may be optionally substituted with
C.sub.1-4 alkyl, where appropriate. In one embodiment the
heterocyclylene group contains only nitrogen heteroatoms.
[1375] In one embodiment, the heterocyclylene group is
unsubstituted. Thus, the hydroxyl and/or --NR.sup.6R.sup.7 groups
are provided elsewhere, as required, for example on -L.sup.1-,
where present, or on -G or -D.
[1376] In one embodiment, the heterocyclylene is connected to
-L.sup.1- or --X-- via a carbon atom or nitrogen atom, where
present, of the heterocyclylene ring.
[1377] In one embodiment, the heterocyclylene is connected to -G
via a carbon atom or nitrogen atom, where present, of
heterocyclylene ring.
[1378] In one embodiment, -L.sup.2- is selected from
piperidinylene, piperazinylene and pyrroldinylene.
[1379] In one embodiment, -L.sup.2- is selected from
piperidinyl-1,4-ene, piperazinyl-1,4-ene and
pyrroldinyl-1,3-ene.
[1380] Location of Hydroxyl and --NR.sup.6R.sup.7 Substituents
[1381] In one embodiment, a group --R.sup.5, such as
G-L.sup.2-L.sup.1- or D-L.sup.1-, may be substituted with one, two
or three hydroxyl groups.
[1382] In one embodiment, --R.sup.5 is substituted with one
hydroxyl group.
[1383] In one embodiment, a group --R.sup.5 may be substituted with
one, two or three groups --NR.sup.6R.sup.7.
[1384] In one embodiment, --R.sup.5 is substituted with one
--NR.sup.6R.sup.7 group.
[1385] In one embodiment, --R.sup.5 is substituted with two or
three groups --NR.sup.6R.sup.7.
[1386] In one embodiment, a group --R.sup.5 may be substituted with
one or two groups --NR.sup.6R.sup.7, and one, two or three hydroxyl
groups.
[1387] In one embodiment, --R.sup.5 is substituted with one
--NR.sup.6R.sup.7 group and one hydroxyl group.
[1388] In one embodiment, a hydroxyl group, such as one, two or
three hydroxyl groups, are substituents to -G.
[1389] In one embodiment, a hydroxyl group, such as one, two or
three hydroxyl groups, are substituents to -D.
[1390] In one embodiment, a hydroxyl group, such as one, two or
three hydroxyl groups, are substituents to -L.sup.1-, where
appropriate, for example where -L.sup.1- is alkylene or
heteroalkylene.
[1391] In one embodiment, a hydroxyl group, such as one, two or
three hydroxyl groups, are substituents to -L.sup.2-, where
appropriate, for example where -L.sup.2- is heterocyclylene.
[1392] In one embodiment, a --NR.sup.6R.sup.7 group, such as one,
two or three --NR.sup.6R.sup.7 groups, are substituents to -G.
[1393] In one embodiment, a --NR.sup.6R.sup.7 group, such as one,
two or three --NR.sup.6R.sup.7 groups, are substituents to -D.
[1394] In one embodiment, a --NR.sup.6R.sup.7 group, such as one,
two or three --NR.sup.6R.sup.7 groups, are substituents to
-L.sup.1-, where appropriate, for example where -L.sup.1- is
alkylene or heteroalkylene.
[1395] In one embodiment, a --NR.sup.6R.sup.7 group, such as one,
two or three --NR.sup.6R.sup.7 groups, are substituents to
-L.sup.2-, where appropriate, for example where -L.sup.2- is
heterocyclylene.
[1396] In one embodiment, G-L.sup.2-L.sup.1- is optionally
substituted with (i), (ii) and (iii), for instance where L.sup.1-
is a nitrogen-containing C.sub.2-12 heteroalkylene and/or -L.sup.2-
is a nitrogen-containing C.sub.4-10 heterocyclylene. In one
embodiment, the proviso does not apply, therefore that (i), (ii)
and (iii) are not optional substituents.
[1397] In one embodiment, G-L.sup.2-L.sup.1- is substituted with:
[1398] (i) one or two hydroxyl groups, or [1399] (ii) one or two
groups --NR.sup.6R.sup.7, or [1400] (iii) one group
--NR.sup.6R.sup.7 and one hydroxyl groups, [1401] with the proviso
that (i), (ii) and (iii) are optional substituents when -L.sup.1-
is a nitrogen-containing C.sub.2-12 heteroalkylene and/or -L.sup.2-
is a nitrogen-containing C.sub.4-10 heterocyclylene.
[1402] For the avoidance of doubt, where a group --R.sup.5 is said
to be substituted with one hydroxyl group (--OH), no further
hydroxyl groups are present within --R.sup.5. Likewise, where a
group --R.sup.5 is said to be substituted with one group
--NR.sup.6R.sup.7, no further groups --NR.sup.6R.sup.7 are present
within --R.sup.5. Similarly, where --R.sup.5 has two or three
hydroxyl or --NR.sup.6R.sup.7 groups, the total number of hydroxyl
or --NR.sup.6R.sup.7 groups is two or three.
[1403] As described herein, where a group --NR.sup.6R.sup.7 is
present, it is preferred that it is not a substituent at a carbon
atom a to the group --X--.
[1404] As described in further detail below, where a hydroxyl group
is present, it is preferred that it is a substituent at a carbon
atom a to the group --X--.
[1405] In one embodiment, where --R.sup.5 has more than one
substituent, the substituents are not located on the same carbon
atom.
[1406] A carboxylic group (--COOH) is not to be construed as a
hydroxyl group in the present case.
[1407] Where -L.sup.1- has more than two carbon atoms present (e.g.
C.sub.2-12 alkylene or C.sub.3-12 heteroalkylene) a substituent,
where present, may be provided at a carbon atom that is .alpha. to
the group --X--.
[1408] Similarly, where -L.sup.1- and -L.sup.2- are both covalent
bonds, and -G is C.sub.2-12 alkyl, the group C.sub.2-12 alkyl may
have a substituent at a carbon atom that is a to the group
--X--.
[1409] In one embodiment, -L.sup.1- is substituted with a hydroxyl
group (for example one, two or three hydroxyl groups) and the
hydroxyl group is provided at the carbon atom that is a to the
group --X--. Examples of compounds having such a substitution
include Example compound 27 in the present case. The present
inventors have found that compounds having a hydroxyl group at the
.alpha. carbon have a particularly improved potentiating activity
compared to those compounds where the hydroxyl group is connected,
for example, to a carbon atom that is not .alpha. the group --X--,
for example .beta. or .gamma. to the group --X--, such as Example
compound 25.
[1410] Similarly, where -L.sup.1- and -L.sup.2- are both covalent
bonds, and -G is C.sub.2-12 alkyl, the group C.sub.2-12 alkyl may
have a hydroxyl group provided at a carbon atom that is a to the
group --X--.
[1411] Where -L.sup.1- has more than two carbon atoms present (e.g.
C.sub.2-12 alkylene or C.sub.3-12 heteroalkylene) a substituent,
where present, may be provided at a carbon atom that is not .alpha.
to the group X. For example, the substituent may be provided at a
carbon atom that is .beta. or .gamma. to the group --X--. In one
embodiment, no substituent is provided at the carbon atom .alpha.
to the group --X--.
[1412] Similarly, where -L.sup.1- and -L.sup.2- are both covalent
bonds, and -G is C.sub.2-12 alkyl, the group C.sub.2-12 alkyl may
have a substituent that is not provided at a carbon atom that is a
to the group --X--. For example, the substituent may be provided at
a carbon atom that is .beta. or .gamma. to the group --X--.
[1413] In one embodiment, -L.sup.1- is substituted with an amino
group (for example one or two amino groups) and the amino group
(i.e. --NR.sup.6R.sup.7) is provided at a carbon atom that is not
.alpha. to the group X. Examples of compounds having such a
substitution include Example compound 10 in the present case. The
present inventors have found that compounds having an amino group
at the .alpha. carbon, such as Example compound 40, have
particularly reduced potentiating activity compared to those
compounds where the amino group is connected, for example, to a
carbon atom that is .gamma. or .gamma. to the group --X--.
[1414] Similarly, where -L.sup.1- and -L.sup.2- are both covalent
bonds, and -G is C.sub.2-12 alkyl, the group C.sub.2-12 alkyl may
have an amino group provided at a carbon atom that is not .alpha.
to the group --X--, for example .beta. or .gamma. to the group
--X--.
[1415] In one embodiment, an amino or hydroxyl substituent is
provided at a terminal carbon of the group -L.sup.1- (e.g.
C.sub.2-12 alkylene or C.sub.2-12 heteroalkylene) or the terminal
carbon of the --C.sub.2-12 alkyl, where present.
[1416] In one embodiment, the group -L.sup.1- in D-L.sup.1- is a
covalent bond. Thus -D, which is a C.sub.4-10 heterocyclyl, is
connected directly to the group --X--.
[1417] In one embodiment, the group -L.sup.2- is a C.sub.4-10
heterocyclyl. Where -L.sup.1- is a covalent bond, -L.sup.2- is
connected directly to the group --X--.
[1418] The connection of either these heterocyclyl groups to --X--
is discussed below.
[1419] In one embodiment, an atom that is a to the group --X-- may
be a ring carbon atom of the heterocyclyl group. A ring heteroatom
of the heterocyclyl group may be covalently bonded to the ring
carbon atom that is a to the group --X-- i.e. the ring heteroatom
is .beta. to the group --X--. In one embodiment, a ring heteroatom
.beta. to the group X is O or S, such as O. In one embodiment the
ring heteroatom .beta. to the group --X-- is not N.
[1420] In one embodiment, a ring heteroatom .gamma. to the group X
is O, S or N.
[1421] In one embodiment, where -L.sup.1- and -L.sup.2- are both
covalent bonds, and -G is a C.sub.5-12 heteroaryl, the heteroaryl
may be connected to the group --X-- via a ring carbon atom, which
is .alpha. to the group --X--). In one embodiment, a ring
heteroatom, such as N, is not connected to the carbon atom which is
a to the group --X--. Alternatively, a ring heteroatom, such as O
or S, is connected to the carbon atom which is .alpha. to the group
--X--.
[1422] In one embodiment, the group G-L.sup.2-L.sup.1- has one, two
or three hydroxyl group and/or --NR.sup.6R.sup.7 substituents.
These substituents may be provided on one or more of the groups
-G-, -L.sup.2- or -L.sup.1-, where appropriate. In one embodiment,
the substituents are provided on -G- and/or -L.sup.1-. Where
-L.sup.1- is C.sub.2-12 heteroalkylene, the one, two or three
hydroxyl group and/or --NR.sup.6R.sup.7 substituents are
optional.
[1423] The group D-L.sup.1- optionally has one, two or three
hydroxyl group and/or --NR.sup.6R.sup.7 substituents.
[1424] Where the substituents are present they may be provided on
-D or -L.sup.1-, where appropriate.
[1425] In one embodiment, --R.sup.5 is G-L.sup.2-L.sup.1-, where -G
is C.sub.5-12 aryl.
[1426] In one embodiment, --R.sup.5 is G-L.sup.2-L.sup.1-, where -G
is C.sub.3-10 cycloalkyl or --C.sub.2-12 alkyl, or --R.sup.5 is
D-L.sup.1-, where D is C.sub.4-10 heterocyclyl.
[1427] In one embodiment, G-L.sup.2-L.sup.1- is substituted with
(i) one, two or three hydroxyl groups, (ii) one, two or three
groups --NR.sup.6R.sup.7, or (iii) one or two groups
--NR.sup.6R.sup.7, and one, two or three hydroxyl groups. Where an
aryl group is present in G-L.sup.2-L.sup.1- it is independently
optionally substituted one or more substituents selected from
--C.sub.1-4 alkyl, halo, --CN, --NO.sub.2, --CF.sub.3,
--NR.sup.10C(O)R.sup.10, --CON(R.sup.10).sub.2, --COOR.sup.9,
--OCOR.sup.10, --NR.sup.10COOR.sup.10, --OCON(R.sup.10).sub.2,
--OCF.sub.3, --NR.sup.10CON(R.sup.10).sub.2, --OR.sup.9,
--SR.sup.9, --NR.sup.10SO.sub.2R.sup.10,
--SO.sub.2N(R.sup.10).sub.2 and --SO.sub.2R.sup.10 where each
--R.sup.9 is independently --C.sub.1-4 alkyl and each --R.sup.10 is
independently --H or --C.sub.1-4 alkyl.
[1428] In one embodiment, D-L.sup.1- is optionally substituted with
(i) one, two or three hydroxyl groups, (ii) one, two or three
groups --NR.sup.6R.sup.7, or (iii) one, two or three groups
--NR.sup.6R.sup.7, and one, two or three hydroxyl groups.
[1429] In one embodiment, D-L.sup.1- is substituted with (i) one,
two or three hydroxyl groups, (ii) one, two or three groups
--NR.sup.6R.sup.7, or (iii) one, two or three groups
--NR.sup.6R.sup.7, and one, two or three hydroxyl groups.
[1430] The groups C.sub.3-10 cycloalkyl C.sub.2-12 alkyl and
C.sub.4-10 heterocyclyl may be substituted with hydroxyl and/or
--NR.sup.6R.sup.7 groups. Where the cycloalkyl or heterocyclyl
groups include a fused aromatic ring, that aromatic ring may be
optionally substituted with the optional substituents described
herein. The optional further substituents do not include hydroxyl
and/or --NR.sup.6R.sup.7 groups.
[1431] The group C.sub.5-12 aryl is substituted with hydroxyl
and/or --NR.sup.6R.sup.7 groups and the C.sub.5-12 aryl group is
optionally further substituted. The optional further substituents
do not include hydroxyl and/or --NR.sup.6R.sup.7 groups.
[1432] It is not essential for the C.sub.3-10 cycloalkyl,
C.sub.2-12 alkyl, C.sub.5-12 aryl and C.sub.4-10 heterocyclyl
groups of -G and -D to be substituted with hydroxyl and/or
--NR.sup.6R.sup.7 groups. In one embodiment, the hydroxyl and/or
--NR.sup.6R.sup.7 groups may be provided on the linker elements of
--R.sup.5 e.g. -L.sup.1- and/or -L.sup.2-, where present.
[1433] Where --R.sup.5 contains a heterocyclyl or heteroalkylene
group, for example as part of -L.sup.1-, -L.sup.2- or -D, such as
nitrogen-containing heterocyclyl or heteroalkylene groups, the
hydroxyl and/or --NR.sup.6R.sup.7 groups may be optional.
[1434] In one embodiment, G-L.sup.2-L.sup.1- is substituted with:
[1435] (i) one, two or three hydroxyl groups, or [1436] (ii) one,
two or three groups --NR.sup.6R.sup.7, or [1437] (iii) one or two
groups --NR.sup.6R.sup.7, and one, two or three hydroxyl groups,
[1438] with the proviso that (i), (ii) and (iii) are optional
substituents when -L.sup.1- is a nitrogen-containing C.sub.2-12
heteroalkylene and/or -L.sup.2- is a nitrogen-containing C.sub.4-10
heterocyclyl.
[1439] In one embodiment, G-L.sup.2-L.sup.1- is substituted with:
[1440] (i) one, two or three hydroxyl groups, or [1441] (ii) one,
two or three groups --NR.sup.6R.sup.7, or [1442] (iii) one or two
groups --NR.sup.6R.sup.7, and one, two or three hydroxyl
groups.
[1443] -D
[1444] The N terminal substituent of the polymyxin compound may
include a C.sub.4-10 heterocyclyl group ("heterocyclyl group").
Thus, in one embodiment, --R.sup.5 includes the group -D, which is
a C.sub.4-10 heterocyclyl.
[1445] In one embodiment, -D is a nitrogen-containing heterocyclyl
group. In such embodiments the hydroxyl and --NR.sup.6R.sup.7
groups are optional.
[1446] Where a heterocyclyl group does not contain a nitrogen atom,
either or both of -D and -L.sup.1- must be substituted with one,
two or three hydroxyl and/or --NR.sup.6R.sup.7 groups or -L.sup.1-
must be a nitrogen-containing C.sub.2-12 heteroalkylene.
[1447] In one embodiment, C.sub.4-10 heterocyclyl is C.sub.4-6 or
C.sub.5-6 heterocyclyl, such as C.sub.5 heterocyclyl or C.sub.6
heterocyclyl.
[1448] In one embodiment, the C.sub.4-10 heterocyclyl contains one
or two heteroatoms selected from N, S and O. Where a S atom is
present, it may be in the form S, S(O) or S(O).sub.2. Where an N
atom is present it may be in the form NH or NR, where R is
C.sub.1-4 alkyl, such as methyl or ethyl.
[1449] In one embodiment, the heterocyclyl group is a
nitrogen-containing heterocyclyl group.
[1450] In one embodiment, the C.sub.4-10 heterocyclyl is
piperidinyl, piperazinyl, morpholinyl, dioxanyl, thiomorpholinyl
(including oxidised thiomorpholinyl), or pyrroldinyl.
[1451] In one embodiment, the C.sub.4-10 heterocyclyl is
piperidinyl, piperazinyl, thiomorpholinyl (including oxidised
thiomorpholinyl), pyrroldinyl or morpholinyl.
[1452] In one embodiment, the C.sub.4-10 heterocyclyl is
piperidinyl, piperazinyl or pyrroldinyl.
[1453] Where a heterocyclyl is present it is connected to -L.sup.1-
or --X-- via a ring carbon atom or a ring N atom, where present. In
one embodiment, the heterocyclyl is connected via a ring carbon
atom. In another embodiment, the heterocyclyl is connected via a
ring nitrogen atom, where present.
[1454] Where a heterocyclyl is substituted with one, two or three
hydroxyl and/or --NR.sup.6R.sup.7 groups, these groups are
substituents to the heterocyclyl ring carbon atoms.
[1455] In one embodiment, a hydroxyl or --NR.sup.6R.sup.7 group,
where present, is a substituent to a ring carbon atom that is
.beta. to a ring heteroatom.
[1456] In one embodiment, the heterocyclyl, if substituted, has a
maximum of one or two substituents, which may be the same or
different.
[1457] In one embodiment, the total number of carbon atoms in the
heterocyclyl group, together with the total number of carbon atoms
present in --R.sup.6 and --R.sup.7 (where present) is at least 5,
at least 6, at least 7 or at least 8.
[1458] For the avoidance of doubt, the index "C.sub.x-y" in terms
such as "C.sub.4-7 heterocyclyl", and the like, refers to the
number of ring atoms, which may be carbon atoms or heteroatoms
(e.g., N, O, S). For example, piperidinyl is an example of a
C.sub.6heterocycyl group.
[1459] The term "heterocyclyl" in reference to the group -D refers
to a group (1) which has one or more heteroatoms (e.g., N, O, S)
forming part of a ring system, wherein the ring system comprises
one ring or two or more fused rings, wherein at least one ring of
the ring system is a non-aromatic ring, and (2) which is attached
to the rest of the molecule by a non-aromatic ring atom (i.e., a
ring atom that is part of a non-aromatic ring that is part of the
ring system). For example: piperidino and piperidin-4-yl are both
examples of a C.sub.6heterocycyl group; 2,3-dihydro-1H-indol-1-yl
is an example of a C.sub.9heterocycyl group; and both
decahydro-quinolin-5-yl and 1,2,3,4-tetrahydroquinolin-4-yl are
examples of a C.sub.10heterocyclyl group.
##STR00278##
[1460] The optional substituents are those described as optional
substituents for the C.sub.5-12 aryl group.
[1461] In one embodiment, where a heterocyclyl group contains two
or more fused rings, each ring is non-aromatic.
[1462] In one embodiment, the heterocyclyl group comprises one
ring.
[1463] -G
[1464] The group -G is selected from C.sub.3-10 cycloalkyl,
C.sub.2-12 alkyl and C.sub.5-12 aryl. A description of each of
these is given below. The groups discussed below may be used
together with any -L.sup.1- and -L.sup.2-, as appropriate.
[1465] C.sub.3-10 cycloalkyl
[1466] The N terminal substituent of the polymyxin compound may
include a C.sub.3-10 cycloalkyl group ("cycloalkyl group"). Thus,
-G may be C.sub.3-10 cycloalkyl.
[1467] When -G is C.sub.3-10 cycloalkyl, -L.sup.1- may be a
covalent bond, C.sub.1-12 alkylene or C.sub.2-10 heteroalkylene,
for example a covalent bond or C.sub.1-12 alkylene.
[1468] When -G is C.sub.3-10 cycloalkyl, -L.sup.2- may be a
covalent bond or C.sub.4-12 heterocyclyl, for example a covalent
bond.
[1469] In one embodiment, C.sub.3-10 cycloalkyl is a C.sub.3-8 or
C.sub.3-6 cycloalkyl.
[1470] In one embodiment, C.sub.3-10 cycloalkyl is cyclopentyl or
cyclohexyl.
[1471] In one embodiment, the cycloalkyl, if substituted, has a
maximum of one or two substituents, which may be the same or
different.
[1472] In one embodiment, the number of substituents on the
cycloalkyl group is no greater than the number of carbon atoms in
the cycloalkyl group. Thus, where the alkyl group is a C.sub.6
alkyl group it may be substituted with no more than six
substituents.
[1473] In one embodiment, the total number of carbon atoms in the
cycloalkyl group, together with the total number of carbon atoms
present in --R.sup.6 and --R.sup.7 (where present) is at least 5,
at least 6, at least 7 or at least 8.
[1474] In one embodiment, the cycloalkyl is cyclohexyl having a
single hydroxyl or --NR.sup.6R.sup.7 group, such as a 4-subsituted
cyclohexyl group. In one embodiment, the cycloalkyl is cyclopentyl
having a single hydroxyl or --NR.sup.6R.sup.7 group, such as a 2-
or 3-subsituted cyclopentyl group.
[1475] In one embodiment, the cycloalkyl is unsubstituted. In this
embodiment, the substituents are located on the linker
-L.sup.2-L.sup.1-, which accordingly cannot be a covalent bond.
[1476] In one embodiment, for example where the core of the
compound of formula (I) is Polymyxin B, the group
G-L.sup.2-L.sup.1- is not 2-aminocyclohexyl, 3-aminocyclohexyl or
4-aminocyclohexyl.
[1477] For the avoidance of doubt, "cycloalkyl" refers to a group
(1) which has a ring system comprising one ring or two or more
fused rings, wherein one ring of the fused ring system may be an
aromatic ring, and (2) which is attached to the rest of the
molecule by a non-aromatic ring atom (i.e., a ring atom that is
part of a non-aromatic ring that is part of the ring system). For
example: cycloalkyl is an example of a C6 cycloalkyl group; and
tetralin-2-yl is an example of a Cio cycloalkyl group.
##STR00279##
[1478] Where an aromatic ring is present, it may be optionally
substituted. The optional substituents are those described as
optional substituents for the C.sub.5-12 aryl group.
[1479] In one embodiment, where the cycloalkyl comprises two or
more fused rings, each ring is non-aromatic.
[1480] In one embodiment, the cycloalkyl group comprises one
ring.
[1481] C.sub.2-12 alkyl
[1482] The N terminal substituent of the polymyxin compound may be
a C.sub.2-12 alkyl group ("alkyl group"). Thus, -G may be
C.sub.2-12 alkyl.
[1483] When -G is C.sub.2-12 alkyl, -L.sup.1- may be a covalent
bond or C.sub.2-10 heteroalkylene, such as a covalent bond.
[1484] When -G is C.sub.2-12 alkyl, -L.sup.2- may be a covalent
bond or C.sub.4-12 heterocyclyl, for example a covalent bond.
[1485] In one embodiment, where -G is C.sub.2-12 alkyl, both
-L.sup.2- and -L.sup.1- are covalent bonds. Thus, -G is connected
directly to --X--.
[1486] In one embodiment, C.sub.2-12 alkyl is C.sub.3-12 alkyl, for
example C.sub.4-12 or C.sub.6-12 alkyl.
[1487] In one embodiment, C.sub.2-12 alkyl is C.sub.2-6 alkyl, for
example C.sub.2-4 alkyl.
[1488] The alkyl group is a saturated, aliphatic alkyl group. The
alkyl group may be a linear or a branched alkyl group.
[1489] In one embodiment, the alkyl group is branched and the
branch is not at the carbon atom that is a to the group -L.sup.2-,
-L.sup.1-, or --X--.
[1490] In one embodiment, the number of substituents on the alkyl
group is no greater than the number of carbon atoms in the alkyl
group. Thus, where the alkyl group is a C.sub.2 alkyl group it may
be substituted with no more than two substituents.
[1491] In one embodiment, the total number of carbon atoms in the
alkyl group, together with the total number of carbon atoms present
in --R.sup.6 and --R.sup.7 (where present) is at least 5, at least
6, at least 7 or at least 8.
[1492] In one embodiment, the alkyl group has a substituent at the
terminal carbon. Terminal carbon refers to a carbon atom that would
be a --CH.sub.3 if it bore no substituents. In a branched alkyl
group this carbon may be the carbon atom that is at the terminal of
the longest linear portion of the alkyl group.
[1493] In one embodiment, the alkyl group has a substituent that is
located at a carbon atom that is .beta. or .gamma. the terminal
carbon atom.
[1494] As noted above, in one embodiment, a --NR.sup.6R.sup.7
group, where present as a substituent to the alkyl group, is a
substituent to a carbon atom that is not .alpha. to the group
-L.sup.2-, -L.sup.1-, or --X--. As noted above, in one embodiment,
a hydroxyl group, where present as a substituent to the alkyl
group, is a substituent to the carbon atom a to the group
-L.sup.2-, -L.sup.1-, or --X--.
[1495] In one embodiment, the alkyl group has no substituent at the
carbon atom a to the group -L.sup.2-, -L.sup.1-, or --X--.
[1496] In one embodiment, the alkyl, if substituted, has a maximum
of one or two substituents, which may be the same or different.
[1497] In alternative aspects of the present invention, the N
terminal substituent of the polymyxin compound is a C.sub.1-12
alkyl group. In one embodiment, --R.sup.5 is C.sub.1-12 alkyl
group, such as C.sub.1 alkyl. Where --R.sup.5 is C.sub.1 alkyl, one
substituent is present, such as one --NR.sup.6R.sup.7 group.
[1498] C.sub.5-12 aryl
[1499] The N terminal substituent of the polymyxin compound may
include or be a C.sub.5-12 aryl group ("a group"). Thus, -G may be
C.sub.5-12 aryl.
[1500] When -G is C.sub.5-12 aryl, -L.sup.1- may be a covalent
bond, C.sub.1-12 alkylene or C.sub.2-10 heteroalkylene, for example
a covalent bond or C.sub.1-12 alkylene.
[1501] When -G is C.sub.5-12 aryl, -L.sup.2- may be a covalent bond
or C.sub.4-12 heterocyclyl, for example a covalent bond.
[1502] The aryl group is optionally substituted, with these
substituents being in addition to any hydroxyl or --NR.sup.6R.sup.7
groups.
[1503] In one embodiment, C.sub.5-12 aryl is C.sub.5-7 aryl
[1504] In one embodiment, C.sub.5-12 aryl is C.sub.6-10 carboaryl
or C.sub.5-12 heteroaryl.
[1505] In one embodiment, C.sub.5-12 aryl is C.sub.6-10
carboaryl.
[1506] In one embodiment, C.sub.6-10 carboaryl is phenyl or
napthyl.
[1507] In one embodiment, C.sub.6-10 carboaryl is phenyl.
[1508] In one embodiment, C.sub.5-12 aryl is C.sub.5-12 heteroaryl,
for example C.sub.5-10, C.sub.5-6, C.sub.5 or C.sub.6
heteroaryl.
[1509] The heteroaryl may contain one or two nitrogen atoms and
additionally or alternatively, where the heteroaryl is a C.sub.5
heteroaryl, it may contain an oxygen or sulfur atom
[1510] In one embodiment, C.sub.5-12 heteroaryl is independently
furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl,
isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl,
pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl or indole.
Additionally or alternatively, the C.sub.5-12 heteroaryl is
independently pyridone.
[1511] Where a heteroaryl is present in group -G it is connected to
-L.sup.1-, -L.sup.2- or --X-- via a ring carbon atom or a ring N
atom, where present. In one embodiment, the heteroaryl is connected
via a ring carbon atom. In another embodiment, the heteroaryl is
connected via a ring nitrogen atom, where present.
[1512] In one embodiment, C.sub.5-12 aryl is phenyl or
pyridine.
[1513] For the avoidance of doubt, "heteroaryl" refers to a group
(1) which has one or more heteroatoms (e.g., N, O, S) forming part
of a ring system, wherein the ring system comprises one ring or two
or more fused rings, wherein at least one ring of the ring system
is an aromatic ring, and (2) which is attached to the rest of the
molecule by an aromatic ring atom (i.e., a ring atom that is part
of an aromatic ring that is part of the ring system). For example:
pyridyl is an example of a C.sub.6heteroaryl group; isoquinolyl is
an example of a C.sub.10heteroaryl group; and
1,2,3,4-tetrahydro-isoquinoline-7-yl is an example of a
C.sub.10heteroaryl group.
##STR00280##
[1514] Where a non-aromatic ring is provided, it has no optional
substituents (though it may be provided with one or more hydroxyl
or --NR.sup.6R.sup.7 groups).
[1515] In one embodiment, where a heteroaryl comprises two or more
fused rings, each ring is an aromatic ring.
[1516] In one embodiment, the heteroaryl group comprises one
aromatic ring.
[1517] A heteroaryl group may also include a pyridonyl group, which
may be regarded as a structure corresponding to a pyridinyl group
having a 2- or 4- hydroxyl substituent.
[1518] Similarly, "carboaryl" refers to a group (1) which has a
ring system comprising one ring or two or more fused rings, wherein
at least one ring of the ring system is an aromatic ring, and (2)
which is attached to the rest of the molecule by an aromatic ring
atom (i.e., a ring atom that is part of an aromatic ring that is
part of the ring system). For example: phenyl is an example of a
C.sub.6 carboaryl group; and tetralin-6-yl is an example of a
C.sub.10 carboaryl group.
##STR00281##
[1519] In one embodiment, where a carboaryl comprises two or more
fused rings, each ring is an aromatic ring.
[1520] Where a non-aromatic ring is present, that ring may be a
carbocycle (such as shown above for tetralin), or the ring may be a
heterocycle, as shown below for the group
dihydrobenzo[b][1,4]dioxin-6-yl.
##STR00282##
[1521] In one embodiment, C.sub.6-12 aryl is not diaminophenyl,
such as 3,5-diaminophenyl, for example when --X-- is --C(O)-- and
when -L.sup.1- and -L.sup.2- and are both covalent bonds.
[1522] In one embodiment, C.sub.5-12 aryl is not trihydroxyphenyl,
such as 3,4,5-trihydroxyphenyl, for example when --X-- is
--C(O)--.
[1523] It is noted that Sandow et al. describe Polymyxin
octapeptides having a modified N terminal. The N terminal group
contains a phenyl group that is optionally substituted by 1, 2 or 3
identical or different groups selected from hydroxyl, alkoxy,
amino, carboxyl, alkylamino and halogen. The phenyl group may be
linked to the N terminal via an alkylene pacer and/or an imino
oxime group. Alternatively, the N terminal group contains a
2-aminothiazol-4-yl group.
[1524] The worked examples in Sandow et al. are limited to
octapeptides having a 2-aminothiazol-4-yl group, a benzyl group or
a 3,4,5-trihydroxyphenyl group. There are no examples where a
nonapeptide or decapeptide are used, and there are no examples
where the N terminal group contains amino functionality.
[1525] It is noted that WO 2012/168820 describes Polymyxin
decapeptides having a modified N terminal. The publication suggests
that the N terminal group could include aryl, aralkyl, heteroaryl
and heteroaralkyl functionality, amongst other options. Aryl and
heteroaryl groups may be linked to another aryl or heteroaryl
group, amongst other options. The linker may be a bond,
--(CH.sub.2).sub.n--, --(CH.sub.2).sub.n--O--(CH.sub.2).sub.p--,
--(CH.sub.2).sub.n--S--(CH.sub.2).sub.p--, or
--(CH.sub.2).sub.n--NR.sup.3--(CH.sub.2).sub.p--, where n is 0, 1,
2 or 3; and p is 0, 1, 2 or 3; and R.sup.3 is H or CH.sub.3.
[1526] The worked examples in WO 2012/168820 are limited to
compounds where one aryl or heteroaryl group is linked directly to
another aryl or heteroaryl group. There are no examples where a
linker is present.
[1527] Aryl Group Substituents
[1528] The group --R.sup.5 may include an aryl group, for example
where -G is C.sub.5-12 aryl or C.sub.3-10 cycloalkyl contains a
fused aromatic ring, or where -D is C.sub.4-10 heterocyclyl
containing a fused aromatic ring.
[1529] Each aryl group is optionally substituted with one or more
substituents.
[1530] Where the aryl group is optionally substituted, there may be
one, two or three optional substituents.
[1531] Where a heteroaryl group is substituted, the substituents
may be provided on a ring carbon atom, for example an aromatic ring
carbon atom.
[1532] Each optional substituent is selected from the list
consisting of --C.sub.1-4 alkyl, halo, --CN, --NO.sub.2,
--CF.sub.3, --NR.sup.10C(O)R.sup.10, --CON(R.sup.10).sub.2,
--COORS, --OCOR.sup.10, --NR.sup.10COOR.sup.10,
--OCON(R.sup.10).sub.2, --OCF.sub.3,
--NR.sup.10CON(R.sup.10).sub.2, --OR.sup.9, --SR.sup.9,
--NR.sup.10SO.sub.2R.sup.10, --SO.sub.2N(R.sup.10).sub.2 and
--SO.sub.2R.sup.10 where each --R.sup.9 is independently
--C.sub.1-4 alkyl and each --R.sup.10 is independently --H or
--C.sub.1-4 alkyl
[1533] In one embodiment, each optional substituent is
independently selected from --C.sub.1-4 alkyl, halo,
--NR.sup.10C(O)R.sup.10, --CON(R.sup.10).sub.2, --COOR.sup.9,
--OCOR.sup.10, --NR.sup.10COOR.sup.10, --OCON(R.sup.10).sub.2,
--OCF.sub.3, --NR.sup.10CON(R.sup.10).sub.2, --OR.sup.9, and
--SR.sup.9, where each --R.sup.9 is independently --C.sub.1-4 alkyl
and each --R.sup.10 is independently --H or --C.sub.1-4 alkyl.
[1534] In one embodiment, each optional substituent is
independently selected from --C.sub.1-4 alkyl and halo.
[1535] In one embodiment, a halo group is --F, --Cl or --Br.
[1536] In one embodiment, where a nitrogen atom is provided in an
aromatic ring, it may be optionally substituted with --R.sup.9 or
--R.sup.10, where appropriate.
[1537] The optional substituents may include a C.sub.1-4 alkyl
group, e.g. --R.sup.9 or --R.sup.10, either alone or as part of a
larger substituent group. It is noted that each C.sub.1-4 alkyl
group present may be substituted with the one, two or three
hydroxyl and/or --NR.sup.6R.sup.7 groups.
[1538] In one embodiment, --R.sup.9 or --R.sup.10 are not
substituted with a hydroxyl or --NR.sup.6R.sup.7 group.
[1539] --R.sup.6 and --R.sup.7
[1540] In one embodiment, each --R.sup.6 and --R.sup.7, where
present, is H.
[1541] In one embodiment, --R.sup.6 is H and --R.sup.7 is alkyl,
such as methyl or ethyl, such as methyl.
[1542] In one embodiment, --R.sup.6 is methyl or ethyl, such as
methyl.
[1543] Where -G is an aryl or cycloalkyl group, --R.sup.6 and
--R.sup.7 may together with the nitrogen atom form a heterocycle,
for example C.sub.4-10 heterocyclyl.
[1544] In one embodiment, the C.sub.4-10 heterocyclyl contains one
or two heteroatoms selected from N, S and O. Where a S atom is
present, it may be in the form S, S(O) or S(O).sub.2. Where an N
atom is present it me be in the form NH or NR, where R is C.sub.1-4
alkyl, such as methyl or ethyl. In one embodiment, the C.sub.4-10
heterocyclyl is piperidinyl, piperazinyl, morpholinyl, dioxanyl,
thiomorpholinyl (including oxidised thiomorpholinyl), or
pyrroldinyl.
[1545] In one embodiment, the C.sub.4-10 heterocyclyl is
piperidinyl, piperazinyl, thiomorpholinyl (including oxidised
thiomorpholinyl), pyrroldinyl or morpholinyl.
[1546] In one embodiment, the C.sub.4-10 heterocyclyl is
piperidinyl, piperazinyl or pyrroldinyl.
[1547] In one embodiment, one group --NR.sup.7R.sup.8, where
present, is a guanidine group, such as --NHC(NH)NH.sub.2.
[1548] --R.sup.9
[1549] In one embodiment, --R.sup.9 is methyl or ethyl.
[1550] In one embodiment, --R.sup.9 is methyl.
[1551] --R.sup.10
[1552] In one embodiment, --R.sup.10 is --H.
[1553] In one embodiment, --R.sup.10 is methyl or ethyl.
[1554] In one embodiment, --R.sup.10 is methyl.
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